MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition by targeting Myc in pulmonary arterial smooth muscle cells
- 261 Downloads
MicroRNAs have been considered to participate in pulmonary arterial hypertension (PAH) and regulate numerous disease pathways in pulmonary vasculature. However, the molecular role in the pathologies has not yet been fully uncovered, particularly in the view of energy metabolism and vascular smooth muscle cell phenotypic regulation. Here, several altered miRNAs are founded in genome-wide miRNA sequencing analysis, in which miR-449a-5p was identified as a probable candidate in hypoxic PAH and verified such a decreasing trend. Moreover, we identify that miR-449a-5p plays critical role in both mitochondria metabolic dysfunction and phenotype transformation of pulmonary arterial smooth muscle cells. Subsequently, we initiate that the transcription factor Myc, which is negatively regulated by miR-449a-5p, results in the aberrant effects contributing to pulmonary arterial smooth muscle cell proliferation. Taken together, we demonstrated that the miR-449a-5p/Myc axis is indispensable for the development and progression of PAH. These results may serve as a significant implication for understanding and treatment of PAH.
• The downregulation of miR-449a-5p occurs in both PAH-PAs and hypoxic PASMCs.
• MiR-449a-5p is involved in hypoxia-induced mitochondria dysfunction of PASMCs.
• MiR-449a-5p inhibits hypoxic phenotypic transition and proliferation of PASMCs.
• The aberrant effects of MiR-449a-5p depend on downstream transcription factor Myc.
• Myc contributes to mitochondria dysfunction and phenotype transformation in PAH.
KeywordsPulmonary arterial hypertension MiR-449a-5p Myc Metabolism Phenotypic transition
This work was supported by grants: National Natural Science Foundation of China (contract grant number: 31820103007, 31771276 and 31471095 to D.Z.), National Natural Science Foundation of China (contract grant number: 31500936 to X. Zheng), National Natural Science Foundation of China (contract grant number: 81873412, 31400353 to C. M.), Wu Liande Youth Science Foundation (contract grant number: WLD-QN1410 to C. M.), Excellent Young Talents Fund Program of Higher Education Institutions of Heilongjiang Province (contract grant number: UNPYSCT-2017047 to C. M.), Returned Overseas Students Funding of Heilongjiang Province (contract grant number: 2017QD0040 to C. M.), and Postdoctoral Research Funding of Heilongjiang Province (contract grant number: LBH-Q17098 to C. M.)
Compliance with ethical standards
All animal care and experimental procedures were performed in accordance with relevant guidelines and regulations and approved by the Institutional Animal Care and Use Committee (IACUC) of Harbin Medical University.
Conflict of interest
The authors declare that they have no conflict of interest.
- 17.Ahuja P, Zhao P, Angelis E, Ruan H, Korge P, Olson A, Wang Y, Jin ES, Jeffrey FM, Portman M, MacLellan WR (2010) Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice. J Clin Invest 120(5):1494–1505CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Grayson AR, Walsh EM, Cameron MJ, Godec J, Ashworth T, Ambrose JM, Aserlind AB, Wang H, Evan GI, Kluk MJ, Bradner JE, Aster JC, French CA (2014) MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33(13):1736–1742CrossRefPubMedGoogle Scholar
- 22.Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146(6):904–917CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Sarkar J, Gou D, Turaka P, Viktorova E, Ramchandran R, Raj JU (2010) MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration. Am J Phys 299(6):L861–L871Google Scholar
- 32.Boucherat O, Peterlini T, Bourgeois A, Nadeau V, Breuils-Bonnet S, Boilet-Molez S, Potus F, Meloche J, Chabot S, Lambert C, Tremblay E, Chae YC, Altieri DC, Sutendra G, Michelakis ED, Paulin R, Provencher S, Bonnet S (2018) Mitochondrial HSP90 accumulation promotes vascular remodeling in pulmonary arterial hypertension. Am J Respir Crit Care Med 198(1):90–103CrossRefPubMedGoogle Scholar
- 35.Venturelli D, Lange B, Narni F, Selleri L, Mariano MT, Torelli U, Gewirtz AM, Calabretta B (1988) Prognostic significance of “short-term” effects of chemotherapy on MYC and histone H3 mRNA levels in acute leukemia patients. Proc Natl Acad Sci U S A 85(10):3590–3594CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51CrossRefPubMedGoogle Scholar
- 37.Yoshida T, Azuma H, Aihara K, Fujimura M, Akaike M, Mitsui T, Matsumoto T (2005) Vascular smooth muscle cell proliferation is dependent upon upregulation of mitochondrial transcription factor A (mtTFA) expression in injured rat carotid artery. Atherosclerosis 178(1):39–47CrossRefPubMedGoogle Scholar