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Targeting Epigenetics in Pulmonary Arterial Hypertension

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Targeting Epigenetics in Inflammatory Lung Diseases

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Abstract

Pulmonary arterial hypertension (PAH) is a fatal and enigmatic disease of the pulmonary circulatory system for which there is currently no cure. The intricate pathogenesis of PAH poses a barrier to identifying novel therapeutic targets, resulting in high morbidity and mortality rates. To identify potential drugs or biomarkers from the bench to the bedside, there is a need to expand the current knowledge of the pathogenesis of PAH. Alternative therapies and treatment strategies may slow down the progression of this disease, but a complete cure requires uncovering the underlying novel mechanisms. Emerging epigenetics-based studies are paving the way for understanding the pathophysiology of several complicated disorders, such as cancer, peripheral hypertension, and asthma. Thus, epigenetic studies may help to comprehend the multifaceted nature of PAH. This chapter compiles the current knowledge and emerging therapeutic and biomarker potential of epigenetic factors, such as DNA methylation, histone modifications, and noncoding RNAs, in PAH. As no animal models can fully recapitulate human PAH features, we highlight the emerging microfluidic lab-on-a-chip (LoC) technology as an excellent model for the disease and testing therapeutics.

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Abbreviations

ABCA1:

ATP binding cassette 1

APOA4:

Apolipoprotein A4

BER:

Base excision repair

BMPR2:

Bone morphogenetic protein type II receptor

BRDP:

Bromodomain-containing protein

CAP:

Concentrated ambient particles

ChIP:

Chromatin immunoprecipitation

COPD:

Chronic obstructive pulmonary disease

DNMT:

DNA methyltransferase

ELISA:

Enzyme-linked immunosorbent assay

HDAC:

Histone deacetyl transferases

HME:

Histone modifying enzymes

IL:

Interleukins

LoC:

Lab-on-a-chip

MBD:

Methyl CpG binding

MCT:

Monocrotaline

OoC:

Organ-on-a-chip

PAC:

Pulmonary arterial cells

PAEC:

Pulmonary endothelial cells

PAH:

Pulmonary arterial hypertension

PARP:

Poly (ADP-ribose) polymerases

PASMC:

Pulmonary arterial smooth muscle cell

PDGF-BB:

Platelet-derived growth factor B

PH:

Pulmonary hypertension

PPI:

Protein–protein interactions

PVOD:

Pulmonary veno-occlusive disease

RAAS:

Renin–angiotensin–aldosterone system

RISC:

RNA-induced silencing complex

RSRS:

Renal sodium retention system

RVLM:

Rostral ventrolateral medulla

SAM:

S-adenyl methionine

SMC:

Smooth muscle cell

SNS:

Sympathetic nervous system

TET:

Ten-eleven translocation

TGF:

Transforming growth factor

TLR:

Toll-like receptors

TNF:

Tumor necrosis factor

UHRF:

Ubiquitin-like, containing PHD and RING finger domain

VEGF:

Vascular endothelial growth factors

References

  1. Thenappan T, et al. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tonelli AR, et al. Causes and circumstances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188(3):365–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Humbert M, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;130(24):2189–208.

    Article  PubMed  Google Scholar 

  4. Humbert M, Ghofrani H-A. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016;71(1):73–83.

    Article  PubMed  Google Scholar 

  5. Giaid A, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328(24):1732–9.

    Article  CAS  PubMed  Google Scholar 

  6. Morrell NW, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circulation. 2001;104(7):790–5.

    Article  CAS  PubMed  Google Scholar 

  7. Perros F, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185(3):311–21.

    Article  PubMed  Google Scholar 

  8. Ma L, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lau EM, et al. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017;14(10):603–14.

    Article  CAS  PubMed  Google Scholar 

  10. Luna R, et al. Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension. Braz J Med Biol Res. 2018;51:e7437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim J-D, et al. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension. Exp Mol Med. 2015;47(7):e175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tuder RM, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25S):D4–D12.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhao L, et al. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation. 2012;126(4):455–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Archer SL, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24):2661–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ho L, et al. Epigenetic mechanisms as emerging therapeutic targets and microfluidic chips application in pulmonary arterial hypertension. Biomedicine. 2022;10(1):170.

    CAS  Google Scholar 

  16. Kim GH, et al. Epigenetic mechanisms of pulmonary hypertension. Pulm Circ. 2011;1(3):347–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang P, et al. miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA. Cell Prolif. 2016;49(4):484–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen T, et al. Loss of microRNA-17∼ 92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med. 2015;191(6):678–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen T, et al. MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents. Mol Ther Nucleic Acids. 2022;29:204–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ali MK, et al. The role of circular RNAs in pulmonary hypertension. Eur Respir J. 2022;

    Google Scholar 

  21. Wojciak-Stothard B et al. A microfluidic chip for pulmonary arterial hypertension. 2021.

    Google Scholar 

  22. Low L, Tagle D. Tissue chips–innovative tools for drug development and disease modeling. Lab Chip. 2017;17(18):3026–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Leung CM, et al. A guide to the organ-on-a-chip. Nat Rev Methods Primers. 2022;2(1):1–29.

    Article  Google Scholar 

  24. Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol. 2014;32(8):760–72.

    Article  CAS  PubMed  Google Scholar 

  25. Ingber DE. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet. 2022;23(8):467–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cheng X, Wang Y, Du L. Epigenetic modulation in the initiation and progression of pulmonary hypertension. Hypertension. 2019;74(4):733–9.

    Article  CAS  PubMed  Google Scholar 

  27. Bisserier M, et al. Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease. Vasc Biol. 2020;2(1):R17–34.

    Article  CAS  PubMed  Google Scholar 

  28. Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med. 2013;91(3):297–309.

    Article  CAS  PubMed  Google Scholar 

  29. Wang A, et al. Substrate stiffness and stretch regulate profibrotic mechanosignaling in pulmonary arterial adventitial fibroblasts. Cell. 2021;10(5):1000.

    Article  CAS  Google Scholar 

  30. Hotchkiss RD. The quantitative separation of purines, pyrimidines, an d nucleosides by paper chromatography. J Biol Chem. 1948;175(1):315–32.

    Article  CAS  PubMed  Google Scholar 

  31. Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development: developmental clocks may depend on the enzymic modification of specific bases in repeated DNA sequences. Science. 1975;187(4173):226–32.

    Article  CAS  PubMed  Google Scholar 

  32. Bestor TH, Verdine GL. DNA methyltransferases. Curr Opin Cell Biol. 1994;6(3):380–9.

    Article  CAS  PubMed  Google Scholar 

  33. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38.

    Article  CAS  PubMed  Google Scholar 

  34. Xie S, et al. Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene. 1999;236(1):87–95.

    Article  CAS  PubMed  Google Scholar 

  35. Hermann A, Goyal R, Jeltsch A. The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem. 2004;279(46):48350–9.

    Article  CAS  PubMed  Google Scholar 

  36. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–26.

    Article  CAS  PubMed  Google Scholar 

  37. Okano M, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–57.

    Article  CAS  PubMed  Google Scholar 

  38. Mayer W, et al. Demethylation of the zygotic paternal genome. Nature. 2000;403(6769):501–2.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang F, et al. Active tissue-specific DNA demethylation conferred by somatic cell nuclei in stable heterokaryons. Proc Natl Acad Sci. 2007;104(11):4395–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bhutani N, Burns DM, Blau HM. DNA demethylation dynamics. Cell. 2011;146(6):866–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tahiliani M, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ito S, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ito S, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Meehan RR, et al. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell. 1989;58(3):499–507.

    Article  CAS  PubMed  Google Scholar 

  45. Nan X, Meehan RR, Bird A. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 1993;21(21):4886–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl CpG-binding proteins. Genet Res. 1998;72(1):59–72.

    Article  Google Scholar 

  47. Bellacosa A, et al. MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. Proc Natl Acad Sci. 1999;96(7):3969–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Petronzelli F, et al. Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase. J Biol Chem. 2000;275(42):32422–9.

    Article  CAS  PubMed  Google Scholar 

  49. Wong E, et al. Mbd4 inactivation increases C→ T transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci. 2002;99(23):14937–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hashimoto H, et al. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature. 2008;455(7214):826–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sharif J, et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007;450(7171):908–12.

    Article  CAS  PubMed  Google Scholar 

  52. Achour M, et al. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene. 2008;27(15):2187–97.

    Article  CAS  PubMed  Google Scholar 

  53. Prokhortchouk A, et al. The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 2001;15(13):1613–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Filion GJ, et al. A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol Cell Biol. 2006;26(1):169–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sasai N, Nakao M, Defossez P-A. Sequence-specific recognition of methylated DNA by human zinc-finger proteins. Nucleic Acids Res. 2010;38(15):5015–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Daniel JM, et al. The p120 ctn-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides. Nucleic Acids Res. 2002;30(13):2911–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics. 2009;1(2):239–59.

    Article  CAS  PubMed  Google Scholar 

  58. Gao F, et al. Global analysis of DNA methylation in hepatocellular carcinoma by a liquid hybridization capture-based bisulfite sequencing approach. Clin Epigenetics. 2015;7(1):1–11.

    Article  Google Scholar 

  59. Perros F, et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2013;187(2):189–96.

    Article  CAS  PubMed  Google Scholar 

  60. Han L, et al. DNA methylation and hypertension: emerging evidence and challenges. Brief Funct Genomics. 2016;15(6):460–9.

    CAS  PubMed  Google Scholar 

  61. DeLalio LJ, Sved AF, Stocker SD. Sympathetic nervous system contributions to hypertension: updates and therapeutic relevance. Can J Cardiol. 2020;36(5):712–20.

    Article  PubMed  Google Scholar 

  62. Ji L, et al. Association between polymorphisms in the renin-angiotensin-aldosterone system genes and essential hypertension in the Han Chinese population. PLoS One. 2013;8(8):e72701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hautefort A, et al. Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension. Oncotarget. 2017;8(32):52995.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Liu D, et al. Hypermethylation of BMPR2 promoter occurs in patients with heritable pulmonary arterial hypertension and inhibits BMPR2 expression. Am J Respir Crit Care Med. 2017;196(7):925–8.

    Article  CAS  PubMed  Google Scholar 

  65. Yan Y, et al. DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension. Sci Adv. 2020;6(50):eaba2470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xu X, et al. A genome-wide methylation study on obesity: differential variability and differential methylation. Epigenetics. 2013;8(5):522–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Smith JA, et al. Epigenomic indicators of age in African Americans. Hereditary Genet Curr Res. 2014;3:3.

    Google Scholar 

  68. Han L, et al. The interactions between alcohol consumption and DNA methylation of the ADD1 gene promoter modulate essential hypertension susceptibility in a population-based, case–control study. Hypertens Res. 2015;38(4):284–90.

    Article  CAS  PubMed  Google Scholar 

  69. Bellavia A, et al. DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments. J Am Heart Assoc. 2013;2(3):e000212.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lehninger AL, Nelson DL, Cox MM. Lehninger principles of biochemistry. Macmillan; 2005.

    Google Scholar 

  71. Redon C, et al. Histone H2a variants H2AX and H2AZ. Curr Opin Genet Dev. 2002;12(2):162–9.

    Article  CAS  PubMed  Google Scholar 

  72. Millis RM. Epigenetics and hypertension. Curr Hypertens Rep. 2011;13(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  73. Gupta S, Yel L. Molecular biology and genetic engineering. Middleton’s Allergy: Principles and Practice. 2013;10:162–18.

    Google Scholar 

  74. Sakabe K, Wang Z, Hart GW. β-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci. 2010;107(46):19915–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nathan D, et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev. 2006;20(8):966–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang Y, et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004;306(5694):279–83.

    Article  CAS  PubMed  Google Scholar 

  77. Nelson CJ, Santos-Rosa H, Kouzarides T. Proline isomerization of histone H3 regulates lysine methylation and gene expression. Cell. 2006;126(5):905–16.

    Article  CAS  PubMed  Google Scholar 

  78. Meng F, et al. Discovery and development of small molecules targeting epigenetic enzymes with computational methods. In: Epi-informatics. Elsevier; 2016. p. 75–112.

    Chapter  Google Scholar 

  79. Gerthoffer W. Epigenetic targets for oligonucleotide therapies of pulmonary arterial hypertension. Int J Mol Sci. 2020;21(23):9222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Irmak M, Sizlan A. Essential hypertension seems to result from melatonin-induced epigenetic modifications in area postrema. Med Hypotheses. 2006;66(5):1000–7.

    Article  CAS  PubMed  Google Scholar 

  81. Morimoto S, et al. Sympathetic activation and contribution of genetic factors in hypertension with neurovascular compression of the rostral ventrolateral medulla. J Hypertens. 1999;17(11):1577–82.

    Article  CAS  PubMed  Google Scholar 

  82. Cohen I, et al. Histone modifiers in cancer: friends or foes? Genes Cancer. 2011;2(6):631–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chelladurai P, et al. Targeting histone acetylation in pulmonary hypertension and right ventricular hypertrophy. Br J Pharmacol. 2021;178(1):54–71.

    Article  CAS  PubMed  Google Scholar 

  85. Li M, et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol. 2011;187(5):2711–22.

    Article  CAS  PubMed  Google Scholar 

  86. Boucherat O, et al. HDAC6: a novel histone deacetylase implicated in pulmonary arterial hypertension. Sci Rep. 2017;7(1):1–14.

    Article  CAS  Google Scholar 

  87. Desjardins CA, Naya FJ. The function of the MEF2 family of transcription factors in cardiac development, cardiogenomics, and direct reprogramming. J Cardiovasc Dev Dis. 2016;3(3):26.

    PubMed  PubMed Central  Google Scholar 

  88. Kim J, et al. Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation. 2015;131(2):190–9.

    Article  PubMed  Google Scholar 

  89. Chelladurai P, Seeger W, Pullamsetti SS. Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives. Eur Respir Rev. 2016;25(140):135–40.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Fuks F, et al. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003;31(9):2305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fuks F, et al. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 2000;24(1):88–91.

    Article  CAS  PubMed  Google Scholar 

  92. Ali MK, Ichimura K, Spiekerkoetter E. Promising therapeutic approaches in pulmonary arterial hypertension. Curr Opin Pharmacol. 2021;59:127–39.

    Article  CAS  PubMed  Google Scholar 

  93. Federici C, et al. Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(2):219–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Provencher S. Olaparib for PAH: a multicenter clinical trial. 2018.

    Google Scholar 

  95. Meloche J, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129(7):786–97.

    Article  CAS  PubMed  Google Scholar 

  96. Provencher S. Apabetalone for pulmonary arterial hypertension: a pilot study. 2018.

    Google Scholar 

  97. Meloche J, et al. Bromodomain-containing protein 4: the epigenetic origin of pulmonary arterial hypertension. Circ Res. 2015;117(6):525–35.

    Article  CAS  PubMed  Google Scholar 

  98. Sun BK, Tsao H. Small RNAs in development and disease. J Am Acad Dermatol. 2008;59(5):725–37.

    Article  PubMed  Google Scholar 

  99. Arasu P, Wightman B, Ruvkun G. Temporal regulation of lin-14 by the antagonistic action of two other heterochronic genes, lin-4 and lin-28. Genes Dev. 1991;5(10):1825–33.

    Article  CAS  PubMed  Google Scholar 

  100. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54.

    Article  CAS  PubMed  Google Scholar 

  101. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855–62.

    Article  CAS  PubMed  Google Scholar 

  102. Reinhart BJ, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901–6.

    Article  CAS  PubMed  Google Scholar 

  103. Cummins J, Velculescu V. Implications of micro-RNA profiling for cancer diagnosis. Oncogene. 2006;25(46):6220–7.

    Article  CAS  PubMed  Google Scholar 

  104. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15–20.

    Article  CAS  PubMed  Google Scholar 

  105. Zeng Y. Principles of micro-RNA production and maturation. Oncogene. 2006;25(46):6156–62.

    Article  CAS  PubMed  Google Scholar 

  106. Zhou G, Chen T, Raj JU. MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2015;52(2):139–51.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Lee A, et al. Therapeutic implications of microRNAs in pulmonary arterial hypertension. BMB Rep. 2014;47(6):311.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Negi V, Chan SY. Discerning functional hierarchies of microRNAs in pulmonary hypertension. JCI insight. 2017;2(5):e91327.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Chen J-Q, et al. The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev. 2016;15(12):1171–80.

    Article  CAS  PubMed  Google Scholar 

  110. Meloche J, et al. Therapeutic potential of microRNA modulation in pulmonary arterial hypertension. Curr Vasc Pharmacol. 2015;13(3):331–40.

    Article  CAS  PubMed  Google Scholar 

  111. Boucherat O, Potus F, Bonnet S. microRNA and pulmonary hypertension. Adv Exp Med Biol. 2015;888:237–52.

    Article  PubMed  Google Scholar 

  112. Santos-Ferreira CA, et al. Micro-RNA analysis in pulmonary arterial hypertension: current knowledge and challenges. Basic Transl Sci. 2020;5(11):1149–62.

    Google Scholar 

  113. Ma W, et al. Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension. Mol Ther Nucleic Acids. 2021;26:678–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhang J, et al. Micro RNA-483 amelioration of experimental pulmonary hypertension. EMBO Mol Med. 2020;12(5):e11303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Xu J, et al. MicroRNAs in pulmonary hypertension, from pathogenesis to diagnosis and treatment. Biomol Ther. 2022;12(4):496.

    CAS  Google Scholar 

  116. Wang Y, et al. Epigenetic regulation and its therapeutic potential in pulmonary hypertension. Front Pharmacol. 2018;9:241.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Carregal-Romero S, et al. MicroRNA nanotherapeutics for lung targeting. Insights into pulmonary hypertension. Int J Mol Sci. 2020;21(9):3253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Haussecker D. Current issues of RNAi therapeutics delivery and development. J Control Release. 2014;195:49–54.

    Article  CAS  PubMed  Google Scholar 

  119. Ohno S, Much S. Junk. in DNA in our genome. Brookhaven Symp Biol. 1972.

    Google Scholar 

  120. Beermann J, et al. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;

    Google Scholar 

  121. Castel SE, Martienssen RA. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013;14(2):100–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Engreitz JM, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature. 2016;539(7629):452–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152(6):1298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Brown CJ, et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992;71(3):527–42.

    Article  CAS  PubMed  Google Scholar 

  125. Derrien T, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22(9):1775–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Statello L, et al. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22(2):96–118.

    Article  CAS  PubMed  Google Scholar 

  127. Lesizza P, et al. Noncoding RNAs in cardiovascular disease, In Nucleic acid nanotheranostics. 2019, Elsevier. p. 43–87.

    Google Scholar 

  128. Ulitsky I, et al. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell. 2011;147(7):1537–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Katayama S, et al. Antisense transcription in the mammalian transcriptome. Science. 2005;309(5740):1564–6.

    Article  PubMed  Google Scholar 

  130. Rearick D, et al. Critical association of ncRNA with introns. Nucleic Acids Res. 2011;39(6):2357–66.

    Article  CAS  PubMed  Google Scholar 

  131. Buratowski S. Transcription. Gene expression--where to start? Science (New York, NY). 2008;322(5909):1804–5.

    Article  CAS  Google Scholar 

  132. Wang D, et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature. 2011;474(7351):390–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Salzman J, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7(2):e30733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Guo C-J, et al. Distinct processing of lncRNAs contributes to non-conserved functions in stem cells. Cell. 2020;181(3):621–36. e22

    Article  CAS  PubMed  Google Scholar 

  135. Quinn JJ, et al. Rapid evolutionary turnover underlies conserved lncRNA–genome interactions. Genes Dev. 2016;30(2):191–207.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Hezroni H, et al. Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep. 2015;11(7):1110–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yao R-W, Wang Y, Chen L-L. Cellular functions of long noncoding RNAs. Nat Cell Biol. 2019;21(5):542–51.

    Article  CAS  PubMed  Google Scholar 

  138. Anderson DM, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160(4):595–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nelson BR, et al. A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science. 2016;351(6270):271–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. 2011;21(6):354–61.

    Article  CAS  PubMed  Google Scholar 

  141. Han Y, et al. Role of long non-coding RNAs in pulmonary arterial hypertension. Cell. 2021;10(8):1892.

    Article  CAS  Google Scholar 

  142. Zahid KR, et al. Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs. Cardiovasc Res. 2020;116(12):1937–47.

    Article  CAS  PubMed  Google Scholar 

  143. Rieg AD, et al. PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK-and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of Guinea pigs. Respir Res. 2018;19(1):1–18.

    Article  Google Scholar 

  144. Nogueira-Ferreira R, et al. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: a network approach. Pulm Pharmacol Ther. 2015;35:8–16.

    Article  CAS  PubMed  Google Scholar 

  145. Wang Z, et al. Long non-coding RNA MEG3 mediates high glucose-induced endothelial cell dysfunction. Int J Clin Exp Pathol. 2018;11(3):1088.

    PubMed  PubMed Central  Google Scholar 

  146. Stuhlmüller B, et al. Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue. Am J Pathol. 2003;163(3):901–11.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Wang S-H, et al. Upregulation of H19 indicates a poor prognosis in gallbladder carcinoma and promotes epithelial-mesenchymal transition. Am J Cancer Res. 2016;6(1):15.

    CAS  PubMed  Google Scholar 

  148. Su H, et al. LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT1R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension. Respir Res. 2018;19(1):1–18.

    Article  Google Scholar 

  149. Gu S, et al. Aberrant expression of long noncoding RNAs in chronic thromboembolic pulmonary hypertension. Mol Med Rep. 2015;11(4):2631–43.

    Article  CAS  PubMed  Google Scholar 

  150. Voellenkle C, et al. Implication of long noncoding RNAs in the endothelial cell response to hypoxia revealed by RNA-sequencing. Sci Rep. 2016;6:24141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zehendner CM, et al. Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRβ. Am J Respir Crit Care Med. 2020;202(10):1445–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Lei S, et al. LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension. Am J Phys Heart Circ Phys. 2020;319(2):H377–91.

    CAS  Google Scholar 

  153. Zhuo Y, et al. Functional polymorphism of lncRNA MALAT1 contributes to pulmonary arterial hypertension susceptibility in Chinese people. Clin Chem Lab Med. 2017;55(1):38–46.

    Article  CAS  PubMed  Google Scholar 

  154. Smaldone MC, Davies BJ. BC-819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers. Curr Opin Mol Ther. 2010;12(5):607–16.

    CAS  PubMed  Google Scholar 

  155. Gomes CP, et al. The function and therapeutic potential of long non-coding RNAs in cardiovascular development and disease. Mol Ther Nucleic Acids. 2017;8:494–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Diener T. Potato spindle tuber virus: a plant virus with properties of a free nucleic acid: III. Subcellular location of PSTV-RNA and the question of whether virions exist in extracts or in situ. Virology. 1971;43(1):75–89.

    Article  CAS  PubMed  Google Scholar 

  157. Diener T. Potato spindle tuber “virus”: IV. A replicating, low molecular weight RNA. Virology. 1971;45(2):411–28.

    Article  CAS  PubMed  Google Scholar 

  158. Wang Q, et al. Circular RNAs in pulmonary hypertension: emerging biological concepts and potential mechanism. Animal Model Exp Med. 2022;5(1):38–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nigro JM, et al. Scrambled exons. Cell. 1991;64(3):607–13.

    Article  CAS  PubMed  Google Scholar 

  160. Wang J, et al. Circular RNAs: a rising star in respiratory diseases. Respir Res. 2019;20(1):1–10.

    Article  Google Scholar 

  161. Kristensen LS, et al. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20(11):675–91.

    Article  CAS  PubMed  Google Scholar 

  162. Jeck WR, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19(2):141–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs. Nat Biotechnol. 2014;32(5):453–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Salzman J, et al. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9(9):e1003777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Memczak S, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–8.

    Article  CAS  PubMed  Google Scholar 

  166. Dong R, et al. Increased complexity of circRNA expression during species evolution. RNA Biol. 2017;14(8):1064–74.

    Article  PubMed  Google Scholar 

  167. Werfel S, et al. Characterization of circular RNAs in human, mouse and rat hearts. J Mol Cell Cardiol. 2016;98:103–7.

    Article  CAS  PubMed  Google Scholar 

  168. Chen W, Schuman E. Circular RNAs in brain and other tissues: a functional enigma. Trends Neurosci. 2016;39(9):597–604.

    Article  CAS  PubMed  Google Scholar 

  169. Li X, Yang L, Chen L-L. The biogenesis, functions, and challenges of circular RNAs. Mol Cell. 2018;71(3):428–42.

    Article  CAS  PubMed  Google Scholar 

  170. Starke S, et al. Exon circularization requires canonical splice signals. Cell Rep. 2015;10(1):103–11.

    Article  CAS  PubMed  Google Scholar 

  171. Zhang Y, et al. Circular intronic long noncoding RNAs. Mol Cell. 2013;51(6):792–806.

    Article  CAS  PubMed  Google Scholar 

  172. Li Z, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22(3):256–64.

    Article  PubMed  Google Scholar 

  173. Ashwal-Fluss R, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56(1):55–66.

    Article  CAS  PubMed  Google Scholar 

  174. Conn SJ, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160(6):1125–34.

    Article  CAS  PubMed  Google Scholar 

  175. Zhang X-O, et al. Complementary sequence-mediated exon circularization. Cell. 2014;159(1):134–47.

    Article  CAS  PubMed  Google Scholar 

  176. Gao Y, et al. Comprehensive identification of internal structure and alternative splicing events in circular RNAs. Nat Commun. 2016;7(1):1–13.

    Article  Google Scholar 

  177. Lee Y, et al. Molecular mechanisms driving mRNA degradation by m6A modification. Trends Genet. 2020;36(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  178. Liu C-X, et al. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell. 2019;177(4):865–80. e21

    Article  CAS  PubMed  Google Scholar 

  179. Hansen TB, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011;30(21):4414–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Lasda E, Parker R. Circular RNAs co-precipitate with extracellular vesicles: a possible mechanism for circRNA clearance. PLoS One. 2016;11(2):e0148407.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Hansen TB, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–8.

    Article  CAS  PubMed  Google Scholar 

  182. Yu C-Y, Kuo H-C. The emerging roles and functions of circular RNAs and their generation. J Biomed Sci. 2019;26(1):1–12.

    Article  CAS  Google Scholar 

  183. Liu C, et al. A narrative review of circular RNAs as potential biomarkers and therapeutic targets for cardiovascular diseases. Ann Transl Med. 2021;9(7):578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Xu S-L, et al. Regulation of circular RNAs act as ceRNA in a hypoxic pulmonary hypertension rat model. Genomics. 2021;113(1):11–9.

    Article  CAS  PubMed  Google Scholar 

  185. Miao R, et al. Microarray expression profile of circular RNAs in chronic thromboembolic pulmonary hypertension. Medicine. 2017;96(27):e7354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Wang J, et al. Characteristics of circular RNA expression in lung tissues from mice with hypoxia-induced pulmonary hypertension. Int J Mol Med. 2018;42(3):1353–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Huang CX, et al. Hsa_circ_0016070/micro-340-5p Axis accelerates pulmonary arterial hypertension progression by upregulating TWIST1 transcription via TCF4/β-catenin complex. J Am Heart Assoc. 2022;11(14):e024147.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Jing X, et al. Circular RNA Sirtuin1 represses pulmonary artery smooth muscle cell proliferation, migration and autophagy to ameliorate pulmonary hypertension via targeting microRNA-145-5p/protein kinase-B3 axis. Bioengineered. 2022;13(4):8759–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Diao W, et al. Evaluating the effect of Circ-Sirt1 on the expression of SIRT1 and its role in pathology of pulmonary hypertension. Cell Transplant. 2022;31:09636897221081479.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Huang Y, et al. Expression and clinical significance of circular RNA hsa_circ_0003416 in pediatric pulmonary arterial hypertension associated with congenital heart disease. J Clin Lab Anal. 2022;36(4):e24273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Li S-S, et al. hsa_circWDR37_016 regulates hypoxia-induced proliferation of pulmonary arterial smooth muscle cells. Cardiovasc Ther. 2022;2022:7292034.

    Article  PubMed  PubMed Central  Google Scholar 

  192. Jiang Y, et al. Circular RNA Calm4 regulates hypoxia-induced pulmonary arterial smooth muscle cells pyroptosis via the Circ-Calm4/miR-124-3p/PDCD6 axis. Arterioscler Thromb Vasc Biol. 2021;41(5):1675–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Ma C, et al. circRNA CDR1as promotes pulmonary artery smooth muscle cell calcification by upregulating CAMK2D and CNN3 via sponging miR-7-5p. Mol Ther Nucleic Acids. 2020;22:530–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Wang Y, et al. Hsa_circ_0002062 promotes the proliferation of pulmonary artery smooth muscle cells by regulating the Hsa-miR-942-5p/CDK6 signaling pathway. Front Genet. 2021;12:1201.

    Google Scholar 

  195. Yuan P, et al. Impact of circGSAP in peripheral blood mononuclear cells on idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2021;203(12):1579–83.

    Article  PubMed  Google Scholar 

  196. Zhang J, et al. Circ-calm4 serves as an miR-337-3p sponge to regulate Myo10 (Myosin 10) and promote pulmonary artery smooth muscle proliferation. Hypertension. 2020;75(3):668–79.

    Article  CAS  PubMed  Google Scholar 

  197. Zhou S, et al. Circular RNA hsa_circ_0016070 is associated with pulmonary arterial hypertension by promoting PASMC proliferation. Mol The Nucleic Acids. 2019;18:275–84.

    Article  CAS  PubMed  Google Scholar 

  198. Guo J, et al. CircATP2B4 promotes hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells via the miR-223/ATR axis. Life Sci. 2020;262:118420.

    Article  CAS  PubMed  Google Scholar 

  199. Jin X, et al. hsa_circNFXL1_009 modulates apoptosis, proliferation, migration, and potassium channel activation in pulmonary hypertension. Mol Ther Nucleic Acids. 2021;23:1007–19.

    Article  CAS  PubMed  Google Scholar 

  200. Guo HM, Liu ZP. Up-regulation of circRNA_0068481 promotes right ventricular hypertrophy in PAH patients via regulating miR-646/miR-570/miR-885. J Cell Mol Med. 2021;25(8):3735–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Duncombe TA, Tentori AM, Herr AE. Microfluidics: reframing biological enquiry. Nat Rev Mol Cell Biol. 2015;16(9):554–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Nguyen T, et al. Point-of-care devices for pathogen detections: the three most important factors to realise towards commercialization. TrAC Trends Anal Chem. 2020;131:116004.

    Article  CAS  Google Scholar 

  203. Nguyen T, et al. From lab on a chip to point of care devices: the role of open source microcontrollers. Micromachines. 2018;9(8):403.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Jayne RK, et al. Direct laser writing for cardiac tissue engineering: a microfluidic heart on a chip with integrated transducers. Lab Chip. 2021;21(9):1724–37.

    Article  CAS  PubMed  Google Scholar 

  205. Zhang B, et al. Advances in organ-on-a-chip engineering. Nat Rev Mater. 2018;3(8):257–78.

    Article  Google Scholar 

  206. Huh D, et al. Reconstituting organ-level lung functions on a chip. Science. 2010;328(5986):1662–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Sin A, Baxter GT, Shuler ML. Animal on a chip: a microscale cell culture analog device for evaluating toxicological and pharmacological profiles. In: Microfluidics and BioMEMS. 2001. SPIE.

    Google Scholar 

  208. Sin A, et al. The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog. 2004;20(1):338–45.

    Article  CAS  PubMed  Google Scholar 

  209. Michas C, et al. Engineering a living cardiac pump on a chip using high-precision fabrication. Sci Adv. 2022;8(16):eabm3791.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Lee G, et al. Single microfluidic electrochemical sensor system for simultaneous multi-pulmonary hypertension biomarker analyses. Sci Rep. 2017;7(1):1–8.

    Google Scholar 

  211. Bogorad MI, et al. Tissue-engineered 3D microvessel and capillary network models for the study of vascular phenomena. Microcirculation. 2017;24(5):e12360.

    Article  Google Scholar 

  212. Sato K, Nitta M, Ogawa A. A microfluidic cell stretch device to investigate the effects of stretching stress on artery smooth muscle cell proliferation in pulmonary arterial hypertension. Inventions. 2018;4(1):1.

    Article  Google Scholar 

  213. Costa PF, et al. Mimicking arterial thrombosis in a 3D-printed microfluidic in vitro vascular model based on computed tomography angiography data. Lab Chip. 2017;17(16):2785–92.

    Article  CAS  PubMed  Google Scholar 

  214. Westein E, et al. Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner. Proc Natl Acad Sci. 2013;110(4):1357–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Nesbitt WS, et al. A shear gradient–dependent platelet aggregation mechanism drives thrombus formation. Nat Med. 2009;15(6):665–73.

    Article  CAS  PubMed  Google Scholar 

  216. Jain A, et al. Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium. Biomed Microdevices. 2016;18(4):1–7.

    Article  CAS  Google Scholar 

  217. Al-Hilal TA, et al. Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application. Lab Chip. 2020;20(18):3334–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Humbert M, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–30.

    Article  PubMed  Google Scholar 

  219. Shapiro S, et al. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest. 2012;141(2):363–73.

    Article  PubMed  Google Scholar 

  220. Chung L, et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Wiley Online Library; 2014.

    Google Scholar 

  221. de Souza Carvalho C, Daum N, Lehr C-M. Carrier interactions with the biological barriers of the lung: advanced in vitro models and challenges for pulmonary drug delivery. Adv Drug Deliv Rev. 2014;75:129–40.

    Article  PubMed  Google Scholar 

  222. Sarkar T, et al. A protocol for fabrication and on-chip cell culture to recreate PAH-afflicted pulmonary artery on a microfluidic device. Micromachines. 2022;13(9):1483.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Mouchaers K, et al. Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil. Eur Respir J. 2010;36(4):800–7.

    Article  CAS  PubMed  Google Scholar 

  224. Ruan H, et al. The acute effects of 30 mg vs 60 mg of intravenous Fasudil on patients with congenital heart defects and severe pulmonary arterial hypertension. Congenit Heart Dis. 2019;14(4):645–50.

    Article  PubMed  Google Scholar 

  225. Budas GR, et al. ASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2018;197(3):373–85.

    Article  CAS  PubMed  Google Scholar 

  226. Roman BL, St. Hilaire C. Catching a disease: a molecular trap as a therapy for pulmonary arterial hypertension. American Thoracic Society; 2016. p. 1047–9.

    Google Scholar 

  227. Yuan JX-J, Rubin LJ. Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Am Heart Assoc. 2005:534–8.

    Google Scholar 

  228. Southgate L, et al. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020;17(2):85–95.

    Article  CAS  PubMed  Google Scholar 

  229. Burton VJ, et al. Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function. Blood, The Journal of the American Society of Hematology. 2011;117(1):333–41.

    CAS  Google Scholar 

  230. Barroso M, et al. Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression. J Biol Chem. 2014;289(22):15350–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Zaiman A, et al. One hundred years of research in the pathogenesis of pulmonary hypertension. Am J Respir Cell Mol Biol. 2005;33(5):425–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Heath D. The rat is a poor animal model for the study of human pulmonary hypertension. Cardioscience. 1992;3(1):1–6.

    CAS  PubMed  Google Scholar 

  233. Robbins IM. Advancing therapy for pulmonary arterial hypertension: can animal models help? American Thoracic Society; 2004. p. 5–6.

    Google Scholar 

  234. Schermuly RT, et al. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011;8(8):443–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Lu C, Verbridge SS. Microfluidic methods for molecular biology, vol. 1. Springer; 2016.

    Google Scholar 

  236. Wu AR, et al. Automated microfluidic chromatin immunoprecipitation from 2,000 cells. Lab Chip. 2009;9(10):1365–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Cao Z, Lu C. A microfluidic device with integrated sonication and immunoprecipitation for sensitive epigenetic assays. Anal Chem. 2016;88(3):1965–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Pezzuto B, et al. Circulating biomarkers in pulmonary arterial hypertension: update and future direction. J Heart Lung Transplant. 2015;34(3):282–305.

    Article  PubMed  Google Scholar 

  239. Asahara T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–6.

    Article  CAS  PubMed  Google Scholar 

  240. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95(4):343–53.

    Article  CAS  PubMed  Google Scholar 

  241. Yan F, et al. Paracrine mechanisms of endothelial progenitor cells in vascular repair. Acta Histochem. 2022;124(1):151833.

    Article  CAS  PubMed  Google Scholar 

  242. Hansmann G, et al. Design and validation of an endothelial progenitor cell capture chip and its application in patients with pulmonary arterial hypertension. J Mol Med. 2011;89(10):971–83.

    Article  PubMed  Google Scholar 

  243. Kraan J, et al. Clinical value of circulating endothelial cell detection in oncology. Drug Discov Today. 2012;17(13–14):710–7.

    Article  PubMed  Google Scholar 

  244. Asosingh K, et al. Letter by Asosingh et al regarding article, “circulating endothelial progenitor cells in patients with eisenmenger syndrome and idiopathic pulmonary arterial hypertension”. Circulation. 2009;119(9):e230.

    Article  PubMed  Google Scholar 

  245. Diller G-P, et al. Response to letter regarding article,“circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension”. Circulation. 2009;119(9):e231.

    Article  Google Scholar 

  246. Toshner M, et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2009;180(8):780–7.

    Article  PubMed  PubMed Central  Google Scholar 

  247. Diller G-P, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation. 2008;117(23):3020–30.

    Article  CAS  PubMed  Google Scholar 

  248. JunHui Z, et al. Reduced number and activity of circulating endothelial progenitor cells in patients with idiopathic pulmonary arterial hypertension. Respir Med. 2008;102(7):1073–9.

    Article  PubMed  Google Scholar 

  249. Fadini GP, et al. Depletion of endothelial progenitor cells may link pulmonary fibrosis and pulmonary hypertension. Am J Respir Crit Care Med. 2007;176(7):724–5.

    Article  PubMed  Google Scholar 

  250. Smadja DM, et al. Circulating endothelial cells: a new candidate biomarker of irreversible pulmonary hypertension secondary to congenital heart disease. Circulation. 2009;119(3):374–81.

    Article  PubMed  Google Scholar 

  251. Sallmon H, et al. Circulating endothelial cell quantification by microfluidics Chip in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2017;56(5):680–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Lee S, et al. Reduced circulating angiogenic cells in Alzheimer disease. Neurology. 2009;72(21):1858–63.

    Article  PubMed  Google Scholar 

  253. Dome B, et al. Circulating endothelial cells, bone marrow-derived endothelial progenitor cells and proangiogenic hematopoietic cells in cancer: from biology to therapy. Crit Rev Oncol Hematol. 2009;69(2):108–24.

    Article  PubMed  Google Scholar 

  254. Ferry MS, Razinkov IA, Hasty J. Microfluidics for synthetic biology: from design to execution. In: Methods in enzymology. Elsevier; 2011. p. 295–372.

    Google Scholar 

  255. Dani K. An integrated microfluidic platform for vascular studies and more efficient preclinical development. Johns Hopkins University; 2020.

    Google Scholar 

  256. Prabhakar P, et al. 3D-printed microfluidics and potential biomedical applications. Front Nanotechnol. 2021;3:609355.

    Article  Google Scholar 

  257. 3D-Microfab. https://www.sdstate.edu/3d-microfabrication-shared-facility.

  258. Deter HS, Hossain T, Butzin NC. Antibiotic tolerance is associated with a broad and complex transcriptional response in E. coli. Sci Rep. 2021;11(1):1–15.

    Article  Google Scholar 

  259. Hossain T, et al. Antibiotic tolerance, persistence, and resistance of the evolved minimal cell, Mycoplasma mycoides JCVI-Syn3B. Iscience. 2021;24(5):102391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Hossain T, Singh A, Butzin NC. Escherichia coli cells are primed for survival before lethal antibiotic stress. Microbiol Spectr. 2023:e01219-23.

    Google Scholar 

  261. Jammes FC, Maerkl SJ. How single-cell immunology is benefiting from microfluidic technologies. Microsyst Nanoeng. 2020;6(1):1–14.

    Article  Google Scholar 

  262. Hisey CL, et al. A versatile cancer cell trapping and 1D migration assay in a microfluidic device. Biomicrofluidics. 2019;13(4):044105.

    Article  PubMed  PubMed Central  Google Scholar 

  263. Delincé MJ, et al. A microfluidic cell-trapping device for single-cell tracking of host–microbe interactions. Lab Chip. 2016;16(17):3276–85.

    Article  PubMed  Google Scholar 

  264. Chung S, et al. Cell migration into scaffolds under co-culture conditions in a microfluidic platform. Lab Chip. 2009;9(2):269–75.

    Article  CAS  PubMed  Google Scholar 

  265. Song JW, Munn LL. Fluid forces control endothelial sprouting. Proc Natl Acad Sci. 2011;108(37):15342–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Young EW, et al. Technique for real-time measurements of endothelial permeability in a microfluidic membrane chip using laser-induced fluorescence detection. Anal Chem. 2010;82(3):808–16.

    Article  CAS  PubMed  Google Scholar 

  267. Douville NJ, et al. Fabrication of two-layered channel system with embedded electrodes to measure resistance across epithelial and endothelial barriers. Anal Chem. 2010;82(6):2505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Shao J, et al. A microfluidic chip for permeability assays of endothelial monolayer. Biomed Microdevices. 2010;12(1):81–8.

    Article  PubMed  Google Scholar 

  269. Reinitz A, et al. Human brain microvascular endothelial cells resist elongation due to shear stress. Microvasc Res. 2015;99:8–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Song JW, et al. Microfluidic endothelium for studying the intravascular adhesion of metastatic breast cancer cells. PLoS One. 2009;4(6):e5756.

    Article  PubMed  PubMed Central  Google Scholar 

  271. Shevkoplyas SS, et al. Direct measurement of the impact of impaired erythrocyte deformability on microvascular network perfusion in a microfluidic device. Lab Chip. 2006;6(7):914–20.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the members of Dr. Butzin’s lab for the critical review of this manuscript and for sharing their experiences. This work is supported by the National Science Foundation Award Numbers 1922542 and 1849206, and by a USDA National Institute of Food and Agriculture Hatch project grant number SD00H653-18/ project accession no. 1015687.

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  1. Department of Biology and Microbiology, South Dakota State University, Brookings, SD, USA

    K. M. Taufiqur Rahman & Nicholas C. Butzin

  2. Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK, USA

    Tanim Islam

  3. Department of Pediatrics, College of Medicine, University of Saskatchewan, Saskatoon, Saskatoon, SK, Canada

    Md Fahmid Islam

  4. Department of Internal Medicine, University of Genoa, Genoa, Italy

    Roberto G. Carbone

  5. Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, USA

    Nicholas C. Butzin

  6. Pre-Professional Health Academic Program, California State University, East Bay, Hayward, CA, USA

    Md Khadem Ali

Authors
  1. K. M. Taufiqur Rahman
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  2. Tanim Islam
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  3. Md Fahmid Islam
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  4. Roberto G. Carbone
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  5. Nicholas C. Butzin
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  6. Md Khadem Ali
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Editor information

Editors and Affiliations

  1. School of Pharmacy, Suresh Gyan University, Jaipur, Rajasthan, India

    Gaurav Gupta

  2. Department of Science, University of Technology Sydney, Ultimo, NSW, Australia

    Brian G. Oliver

  3. Discipline of Pharmacy, University of Technology Sydney, Schofields, NSW, Australia

    Kamal Dua

  4. Division of Pulmonary and Critical Care Medicine, Stanford Medicine, Stanford, CA, USA

    Md Khadem Ali

  5. School of Pharmacy, Gyan Vihar University, Jaipur, Rajasthan, India

    Piyush Dave

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© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

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Rahman, K.M.T., Islam, T., Islam, M.F., Carbone, R.G., Butzin, N.C., Ali, M.K. (2023). Targeting Epigenetics in Pulmonary Arterial Hypertension. In: Gupta, G., Oliver, B.G., Dua, K., Ali, M.K., Dave, P. (eds) Targeting Epigenetics in Inflammatory Lung Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-99-4780-5_14

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