Statins Improve Endothelial Function Via Suppression of Epigenetic-driven EndMT

Overview

Journal Nat Cardiovasc Res

Publisher Springer Nature

Specialty Cardiology & Vascular Diseases

Date 2023 Sep 11

PMID 37693816

Authors

Chun Liu

Mengcheng Shen

Wilson L W Tan

Ian Y Chen

Yu Liu

Xuan Yu

Huaxiao Yang

Angela Zhang

Yanxia Liu

Ming-Tao Zhao

Mohamed Ameen

Mao Zhang

Eric R Gross

Lei S Qi

Nazish Sayed

Joseph C Wu

Affiliations

Soon will be listed here.

Abstract

The pleiotropic benefits of statins in cardiovascular diseases that are independent of their lipid-lowering effects have been well documented, but the underlying mechanisms remain elusive. Here we show that simvastatin significantly improves human induced pluripotent stem cell-derived endothelial cell functions in both baseline and diabetic conditions by reducing chromatin accessibility at transcriptional enhanced associate domain elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Inhibition of geranylgeranyltransferase (GGTase) I, a mevalonate pathway intermediate, repressed YAP nuclear translocation and YAP activity via RhoA signaling antagonism. We further identified a previously undescribed enhancer downstream of statin-YAP signaling that promotes the EndMT process. Thus, inhibition of any component of the GGTase-RhoA-YAP-SRY box transcription factor 9 (SOX9) signaling axis was shown to rescue EndMT-associated endothelial dysfunction both in vitro and in vivo, especially under diabetic conditions. Overall, our study reveals an epigenetic modulatory role for simvastatin in repressing EndMT to confer protection against endothelial dysfunction.

Citing Articles

Statins as Secondary Preventive Agent to Limit Breast Cancer Metastatic Outgrowth.

Atale N, Wells A Int J Mol Sci. 2025; 26(3).

PMID: 39941069 PMC: 11818786. DOI: 10.3390/ijms26031300.

Lipoprotein(a) and Atrial Fibrillation: Mechanistic Insights and Therapeutic Approaches.

Zhang Z, Peng B, Nuranmubieke A, Xu Y, Liu Y, Tu T Int J Med Sci. 2025; 22(2):357-370.

PMID: 39781530 PMC: 11704704. DOI: 10.7150/ijms.102301.

Chronic inflammation and vascular cell plasticity in atherosclerosis.

Lin A, Miano J, Fisher E, Misra A Nat Cardiovasc Res. 2024; 3(12):1408-1423.

PMID: 39653823 DOI: 10.1038/s44161-024-00569-y.

Transcriptomic analysis of nicotine on the cardiovascular system using a diverse population of human induced pluripotent stem cell-derived endothelial cells.

Jimenez-Tellez N, Williams D, Liu Y, Wang M, Chandy M, Wu J J Mol Cell Cardiol. 2024; 198:21-23.

PMID: 39608091 PMC: 11890120. DOI: 10.1016/j.yjmcc.2024.11.001.

Investigating Inherited Heart Diseases Using Human Induced Pluripotent Stem Cell-Based Models.

Wang B Life (Basel). 2024; 14(11).

PMID: 39598169 PMC: 11595871. DOI: 10.3390/life14111370.

References

Li Y, Lui K, Zhou B . Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases. Nat Rev Cardiol. 2018; 15(8):445-456. DOI: 10.1038/s41569-018-0023-y. View

Antonopoulos A, Margaritis M, Lee R, Channon K, Antoniades C . Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012; 18(11):1519-30. PMC: 3394171. DOI: 10.2174/138161212799504803. View

Zhang H, Liu C, Zha Z, Zhao B, Yao J, Zhao S . TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem. 2009; 284(20):13355-13362. PMC: 2679435. DOI: 10.1074/jbc.M900843200. View

Sen-Banerjee S, Mir S, Lin Z, Hamik A, Atkins G, Das H . Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation. 2005; 112(5):720-6. DOI: 10.1161/CIRCULATIONAHA.104.525774. View

Jiang Y, Jimenez J, Ou K, McCormick M, Zhang L, Davies P . Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo. Circ Res. 2014; 115(1):32-43. PMC: 4065854. DOI: 10.1161/CIRCRESAHA.115.303883. View

Wang X, Valls A, Schermann G, Shen Y, Moya I, Castro L . YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis. Dev Cell. 2017; 42(5):462-478.e7. DOI: 10.1016/j.devcel.2017.08.002. View

Tikoo K, Patel G, Kumar S, Karpe P, Sanghavi M, Malek V . Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem Pharmacol. 2014; 93(3):343-51. DOI: 10.1016/j.bcp.2014.11.013. View

Feig J, Shang Y, Rotllan N, Vengrenyuk Y, Wu C, Shamir R . Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLoS One. 2011; 6(12):e28534. PMC: 3232231. DOI: 10.1371/journal.pone.0028534. View

Liu C, Oikonomopoulos A, Sayed N, Wu J . Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development. 2018; 145(5). PMC: 5868991. DOI: 10.1242/dev.156166. View

10.

Lin Q, Zhao J, Zheng C, Chun J . Roles of notch signaling pathway and endothelial-mesenchymal transition in vascular endothelial dysfunction and atherosclerosis. Eur Rev Med Pharmacol Sci. 2018; 22(19):6485-6491. DOI: 10.26355/eurrev_201810_16062. View

11.

Maruyama J, Inami K, Michishita F, Jiang X, Iwasa H, Nakagawa K . Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth. Mol Cancer Res. 2017; 16(2):197-211. DOI: 10.1158/1541-7786.MCR-17-0382. View

12.

Sayed N, Liu C, Ameen M, Himmati F, Zhang J, Khanamiri S . Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy. Sci Transl Med. 2020; 12(554). PMC: 7557117. DOI: 10.1126/scitranslmed.aax9276. View

13.

Atkins G, Jain M . Role of Krüppel-like transcription factors in endothelial biology. Circ Res. 2007; 100(12):1686-95. DOI: 10.1161/01.RES.0000267856.00713.0a. View

14.

Chen L, Liu Z . Multifaceted function of YAP/TEAD on chromatin:prospects of 'A non-canonical role of YAP/TEAD is required for activation of estrogen-regulated enhancers in breast cancer'. J Mol Cell Biol. 2019; 11(12):1101-1103. PMC: 6934152. DOI: 10.1093/jmcb/mjz106. View

15.

Juarez D, Fruman D . Targeting the Mevalonate Pathway in Cancer. Trends Cancer. 2020; 7(6):525-540. PMC: 8137523. DOI: 10.1016/j.trecan.2020.11.008. View

16.

Laufs U, La Fata V, Plutzky J, Liao J . Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97(12):1129-35. DOI: 10.1161/01.cir.97.12.1129. View

17.

Xin M, Kim Y, Sutherland L, Qi X, McAnally J, Schwartz R . Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011; 4(196):ra70. PMC: 3440872. DOI: 10.1126/scisignal.2002278. View

18.

von Gise A, Pu W . Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ Res. 2012; 110(12):1628-45. PMC: 3427736. DOI: 10.1161/CIRCRESAHA.111.259960. View

19.

Lau E, Paik D, Wu J . Systems-Wide Approaches in Induced Pluripotent Stem Cell Models. Annu Rev Pathol. 2018; 14:395-419. PMC: 6450651. DOI: 10.1146/annurev-pathmechdis-012418-013046. View

20.

Kovacic J, Dimmeler S, Harvey R, Finkel T, Aikawa E, Krenning G . Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019; 73(2):190-209. PMC: 6865825. DOI: 10.1016/j.jacc.2018.09.089. View