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RUNX3 is up-regulated in abdominal aortic aneurysm and regulates the function of vascular smooth muscle cells by regulating TGF-β1

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Abstract

Abdominal aortic aneurysm (AAA) has been associated with the dysfunction of vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) remodelling. Runt-related transcription factor 3 (RUNX3) has been reported to be up-regulated in aneurysmal aorta samples compared with normal aorta. However, its function in VSMCs and the mechanism of function remains unknown. Therefore, our study aimed to investigate the role of RUNX3 in ECM remodelling and VSMC function, and further explore the underlying mechanism. Our results verified that RUNX3 was increased in aortic samples of AAA compared with healthy controls. Overexpression vectors of RUNX3 (ov-RUNX3) and siRNA of RUNX3 (si-RUNX3) were transfected into Human aortic smooth muscle cells (HAoSMCs). The results indicated that ov-RUNX3 promoted cell proliferation, migration, and MMP-2/3/9 secretion, and suppressed TIMP-1, collagen I/III, SM22, MYH11 and CNN1 expression in HAoSMCs. The silencing of RUNX3 has the opposite effect. Furthermore, we found that RUNX3 targets TGF-β1 and suppressed its transcription. The silencing of TGF-β1 increased cell proliferation, migration and MMP-2/3/9 expression, and inhibited TIMP-1, Collagen I/III, SM22, MYH11 and CNN1 expression. In addition, TGF-β1 reversed the effect of RUNX3 overexpression on HAoSMCs. Hence, our study indicated that RUNX3 promotes cell proliferation, migration, and ECM remodelling through suppressing TGF-β1.

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Data availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Abbreviations

AAA:

Abdominal aortic aneurysm

ECM:

Extracellular matrix

VSMCs:

Vascular smooth muscle cells

MMPs:

Matrix metalloproteinases

TIMP-1:

Tissue inhibitor of metalloproteinases 1

RUNX:

Runt related transcription factors

HAoSMCs:

Human aortic smooth muscle cells

OV-RUNX3:

Overexpression vectors of RUNX3

si-RUNX3:

RUNX3 siRNA oligo duplex

References

  • Angelov SN, Hu JH, Wei H, Airhart N, Shi M, Dichek DA (2017) TGF-β (transforming growth factor-β) signaling protects the thoracic and abdominal aorta from angiotensin II-induced pathology by distinct mechanisms. Arterioscler Thromb Vasc Biol 37:2102–2113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen C, Wang Y, Cao Y, Wang Q, Anwaier G, Zhang Q, Qi R (2020) Mechanisms underlying the inhibitory effects of probucol on elastase-induced abdominal aortic aneurysm in mice. Br J Pharmacol 177:204–216

    Article  CAS  PubMed  Google Scholar 

  • Chuang LS, Ito K, Ito Y (2013) RUNX family: regulation and diversification of roles through interacting proteins. Int J Cancer 132:1260–1271

    Article  CAS  PubMed  Google Scholar 

  • Date Y, Ito K (2020) Oncogenic RUNX3: a link between p53 deficiency and MYC dysregulation. Mol Cells 43:176–181

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deguchi JO, Huang H, Libby P, Aikawa E, Whittaker P, Sylvan J, Lee RT, Aikawa M (2009) Genetically engineered resistance for MMP collagenases promotes abdominal aortic aneurysm formation in mice infused with angiotensin II. Lab Invest 89:315–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doyle AJ, Redmond EM, Gillespie DL, Knight PA, Cullen JP, Cahill PA, Morrow DJ (2015) Differential expression of Hedgehog/Notch and transforming growth factor-β in human abdominal aortic aneurysms. J Vasc Surg 62:464–470

    Article  PubMed  Google Scholar 

  • Dubis J, Litwin M, Michalowska D, Zuk N, Szczepanska-Buda A, Grendziak R, Baczynska D, Barc P, Witkiewicz W (2016) Elevated expression of runt-related transcription factors in human abdominal aortic aneurysm. J Biol Regul Homeost Agents 30:497–504

    CAS  PubMed  Google Scholar 

  • Golledge J (2019) Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol 16:225–242

    Article  PubMed  Google Scholar 

  • Guirguis-Blake JM, Beil TL, Senger CA, Coppola EL (2019) Primary care screening for abdominal aortic aneurysm: updated evidence report and systematic review for the US preventive services task force. JAMA 322:2219–2238

    Article  PubMed  Google Scholar 

  • Guo C, Yao F, Wu K, Yang L, Zhang X, Ding J (2010) Chromatin immunoprecipitation and association study revealed a possible role of Runt-related transcription factor 3 in the ulcerative colitis of Chinese population. Clin Immunol 135:483–489

    Article  CAS  PubMed  Google Scholar 

  • Hadi T, Boytard L, Silvestro M, Alebrahim D, Jacob S, Feinstein J, Barone K, Spiro W, Hutchison S, Simon R, Rateri D, Pinet F, Fenyo D, Adelman M, Moore KJ, Eltzschig HK, Daugherty A, Ramkhelawon B (2018) Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nat Commun 9:5022

    Article  PubMed  PubMed Central  Google Scholar 

  • He X, Wang S, Li M, Zhong L, Zheng H, Sun Y, Lai Y, Chen X, Wei G, Si X, Han Y, Huang S, Li X, Liao W, Liao Y, Bin J (2019) Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis. Theranostics 9:5558–5576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu W, Wang Z, Li Q, Wang J, Li L, Jiang G (2019) Upregulation of lincRNA-p21 in thoracic aortic aneurysms is involved in the regulation of proliferation and apoptosis of vascular smooth muscle cells by activating TGF-β1 signaling pathway. J Cell Biochem 120:4113–4120

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Shen Z, Chen Q, Huang P, Zhang H, Du S, Geng B, Zhang C, Li K, Tang C, Du J, Jin H (2016) Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells. Sci Rep 6:19503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones JA, Spinale FG, Ikonomidis JS (2009) Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. J Vasc Res 46:119–137

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Kim MY, Jin H, Kim HJ, Kang SS, Kim HJ, Lee JH, Chang KC, Hwang JY, Yabe-Nishimura C, Kim JH, Seo HG (2009) Peroxisome proliferator-activated receptor delta regulates extracellular matrix and apoptosis of vascular smooth muscle cells through the activation of transforming growth factor-{beta}1/Smad3. Circ Res 105:16–24

    Article  CAS  PubMed  Google Scholar 

  • Kim BR, Kang MH, Kim JL, Na YJ, Park SH, Lee SI, Kang S, Joung SY, Lee SY, Lee DH, Min BW, Oh SC (2016) RUNX3 inhibits the metastasis and angiogenesis of colorectal cancer. Oncol Rep 36:2601–2608

    Article  CAS  PubMed  Google Scholar 

  • Klaus V, Tanios-Schmies F, Reeps C, Trenner M, Matevossian E, Eckstein HH, Pelisek J (2017) Association of matrix metalloproteinase levels with collagen degradation in the context of abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 53:549–558

    Article  CAS  PubMed  Google Scholar 

  • Lee CW, Chuang LS, Kimura S, Lai SK, Ong CW, Yan B, Salto-Tellez M, Choolani M, Ito Y (2011) RUNX3 functions as an oncogene in ovarian cancer. Gynecol Oncol 122:410–417

    Article  CAS  PubMed  Google Scholar 

  • Lenk GM, Tromp G, Weinsheimer S, Gatalica Z, Berguer R, Kuivaniemi H (2007) Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms. BMC Genomics 8:237

    Article  PubMed  PubMed Central  Google Scholar 

  • Li FF, Shang XK, Du XL, Chen S (2018) Rapamycin treatment attenuates angiotensin II -induced abdominal aortic aneurysm formation via VSMC phenotypic modulation and down-regulation of ERK1/2 activity. Curr Med Sci 38:93–100

    Article  CAS  PubMed  Google Scholar 

  • Li X, Zhong M, Wang J, Wang L, Lin Z, Cao Z, Huang Z, Zhang F, Li Y, Liu M, Ma X (2019) miR-301a promotes lung tumorigenesis by suppressing Runx3. Mol Cancer 18:99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Zhao Z, Cai Z, Sun Y, Li L, Yao F, Yang L, Zhou Y, Zhu H, Fu Y, Wang L, Fang W, Chen Y, Kong W (2020) Runx2 (runt-related transcription factor 2)-mediated microcalcification is a novel pathological characteristic and potential mediator of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 40:1352–1369

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Li B, Wang Y, Wang D, Zou J, Ke X, Hao Y (2016) Knockdown of RUNX3 inhibits hypoxia-induced endothelial-to-mesenchymal transition of human cardiac microvascular endothelial cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 32:1627–1631

    PubMed  Google Scholar 

  • Liu Y, Zou J, Li B, Wang Y, Wang D, Hao Y, Ke X, Li X (2017) RUNX3 modulates hypoxia-induced endothelial-to-mesenchymal transition of human cardiac microvascular endothelial cells. Int J Mol Med 40:65–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lotem J, Levanon D, Negreanu V, Bauer O, Hantisteanu S, Dicken J, Groner Y (2017) Runx3 in immunity, inflammation and cancer. Adv Exp Med Biol 962:369–393

    Article  CAS  PubMed  Google Scholar 

  • Milner JJ, Toma C, Yu B, Zhang K, Omilusik K, Phan AT, Wang D, Getzler AJ, Nguyen T, Crotty S, Wang W, Pipkin ME, Goldrath AW (2017) Runx3 programs CD8(+) T cell residency in non-lymphoid tissues and tumours. Nature 552:253–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20:556–567

    Article  CAS  PubMed  Google Scholar 

  • Rabkin SW (2014) Differential expression of MMP-2, MMP-9 and TIMP proteins in thoracic aortic aneurysm - comparison with and without bicuspid aortic valve: a meta-analysis. Vasa 43:433–442

    Article  PubMed  Google Scholar 

  • Rabkin SW (2017) The role matrix metalloproteinases in the production of aortic aneurysm. Prog Mol Biol Transl Sci 147:239–265

    Article  CAS  PubMed  Google Scholar 

  • Rahmanian N, Tarighi P, Gharghabi M, Torshabi M, Tarfiei GA, Mohammadi Farsani T, Ostad SN, Ghahremani MH (2017) Truncated forms of RUNX3 unlike full length protein alter cell proliferation in a TGF-β context dependent manner. Iran J Pharm Res 16:1194–1203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Song H, Xu T, Feng X, Lai Y, Yang Y, Zheng H, He X, Wei G, Liao W, Liao Y (2020) Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. EBioMedicine 57:102832

    Article  PubMed  PubMed Central  Google Scholar 

  • Spin JM, Hsu M, Azuma J, Tedesco MM, Deng A, Dyer JS, Maegdefessel L, Dalman RL, Tsao PS (2011) Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm. Physiol Genomics 43:993–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun J, Li B, Jia Z, Zhang A, Wang G, Chen Z, Shang Z, Zhang C, Cui J, Yang W (2018) RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway. J Neurooncol 140:15–26

    Article  CAS  PubMed  Google Scholar 

  • Van Doren SR (2015) Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol 44–46:224–231

    Article  PubMed  Google Scholar 

  • Wagenseil JE, Mecham RP (2009) Vascular extracellular matrix and arterial mechanics. Physiol Rev 89:957–989

    Article  CAS  PubMed  Google Scholar 

  • Wang YD, Liu ZJ, Ren J, Xiang MX (2018) Pharmacological therapy of abdominal aortic aneurysm: an update. Curr Vasc Pharmacol 16:114–124

    Article  CAS  PubMed  Google Scholar 

  • Weersma RK, Zhou L, Nolte IM, van der Steege G, van Dullemen HM, Oosterom E, Bok L, Peppelenbosch MP, Faber KN, Kleibeuker JH, Dijkstra G (2008) Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5. Inflamm Bowel Dis 14:1615–1622

    Article  PubMed  Google Scholar 

  • Xu X, Zhang F, Lu Y, Yu S, Sun W, Sun S, Cheng J, Ma J, Zhang M, Zhang C, Zhang Y, Zhang K (2019) Silencing of NONO inhibits abdominal aortic aneurysm in apolipoprotein E-knockout mice via collagen deposition and inflammatory inhibition. J Cell Mol Med 23:7449–7461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xue J, Wu X, Qu M, Guo F, Han L, Sun G, Yuan Z, Fan S, Li T (2020) RUNX3 inhibits the invasion and metastasis of human colon cancer HT-29 cells by upregulating MMP-2/9. Evid Based Complement Alternat Med 2020:5978131

    Article  PubMed  PubMed Central  Google Scholar 

  • Xue M, Li G, Li D, Wang Z, Mi L, Da J, Jin X (2019) Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production. Biosci Rep. https://doi.org/10.1042/BSR20191252

  • Zhang Y, Wang S, Lai Q, Fang Y, Wu C, Liu Y, Li Q, Wang X, Gu C, Chen J, Cai J, Li A, Liu S (2020) Cancer-associated fibroblasts-derived exosomal miR-17-5p promotes colorectal cancer aggressive phenotype by initiating a RUNX3/MYC/TGF-β1 positive feedback loop. Cancer Lett 491:22–35

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Vascular Surgery, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, No. 70 Heping Road, Huancui District, Weihai, 264200, China

    Zhongxiao Zhou, Haimeng Zhou, Xin Zou & Xiaowei Wang

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  1. Zhongxiao Zhou
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  2. Haimeng Zhou
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  3. Xin Zou
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  4. Xiaowei Wang
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Contributions

ZZ and HZ: conception, design and analysis of data, performed the data analyses, and wrote the manuscript. XZ: contributed to the conception of the study. XW: contributed significantly to analysis and manuscript preparation. All authors contributed to interpretation of date and review of the manuscript, and approved this manuscript for submission.

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Correspondence to Haimeng Zhou.

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Zhou, Z., Zhou, H., Zou, X. et al. RUNX3 is up-regulated in abdominal aortic aneurysm and regulates the function of vascular smooth muscle cells by regulating TGF-β1. J Mol Histol 53, 1–11 (2022). https://doi.org/10.1007/s10735-021-10035-9

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