Cardiology; Cardiovascular Diseases; Pharmacology; Vascular Diseases; Signal Transduction
Cardiovascular Medicine: Martin Lab
Our overall goal is to understand how regulation of the muscular layer of blood vessels contributes to normal vessel function and to cardiovascular disease. Hyperproliferation or dysfunction in vascular smooth muscle cells contributes to atherosclerosis, hypertension, organ transplant failure, and failure of revascularization therapies such as balloon angioplasty or bypass surgery. By understanding the regulatory mechanisms of vascular smooth muscle, we aim to develop new therapies for treatment and prevention of cardiovascular diseases.
Specialized Terms: Vascular smooth muscle; Differentiation; Signal transduction; Transcription; Epigenetics
Extensive Research Description
Brief Research Summary
Our studies are aimed at understanding the molecular mechanisms that regulate vascular smooth muscle cell (SMC) phenotype. Mature SMC retain the ability to de-differentiate and re-enter the cell cycle. This is essential for such processes as angiogenesis, but also contributes to the pathogenesis of atherosclerosis, intimal hyperplasia, and restenosis.
Regulation of Vascular Smooth Muscle Phenotype: Rapamycin-eluting stents have revolutionized treatment of coronary artery disease, dramatically reducing restenosis. While highly efficacious in this localized drug delivery setting, systemic high dose rapamycin is not a viable strategy for other vascular diseases due to adverse effects. Our goal is to understand the molecular mechanisms by which rapamycin beneficially affects SMC phenotype, in order to develop novel therapeutics. Identifying the smooth muscle-specific targets of the mTOR pathway may generate new therapeutic strategies for treatment and prevention of atherosclerosis and intimal hyperplasia.
Epigentic regulation: We have recently discovered that the mTOR pathway promotes VSMC differentiation through regulation of the DNA modifying enzyme TET2. We have identified TET2 as a novel master epigenetic regulator of VSMC phenotype. Notably, TET2 promotes changes in chromatin that lead to expression of prodifferentiation genes including SRF and myocardin and contractile genes such as SM-MHC and SM-alpha actin, while concomitantly downregulating expression of de-differentiation-associated genes including KFL4.
Akt signaling: We have previously shown that rapamycin feedback signaling through Akt2 underlies its effects on VSMC phenotype in vitro. We are currently studying the effects of Akt isoforms in rapamycin therapeutic response in vivo and have uncovered exciting Akt isoform-specific effects that reveal opposing roles for these nhighly related kinases. We are also studying Akt-regulated transcription factors and cyto skeletal-associated proteins that contribute to VSMC phenotypic modulation.
Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity.
Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation. 2013;128(18):2047-57. Epub 2013/10/01. Circulation. 2013 Sep 27. [Epub ahead of print]
Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition.
Fetalvero KM, Zhang P, Shyu M, Young BT, Hwa J, Young RC, Martin KA. J Clin Invest. 2008;118(12):3966-79. Epub 2008/11/27.
Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling.
Martin KA, Merenick BL, Ding M, Fetalvero KM, Rzucidlo EM, Kozul CD, Brown DJ, Chiu HY, Shyu M, Drapeau BL, Wagner RJ, Powell RJ. J Biol Chem. 2007;282(49):36112-20. Epub 2007/10/03.
Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition.
Xie Y, Jin Y, Merenick BL, Ding M, Fetalvero KM, Wagner RJ, Mai A, Gleim S, Tucker DF, Birnbaum MJ, Ballif BA, Luciano AK, Sessa WC, Rzucidlo EM, Powell RJ, Hou L, Zhao H, Hwa J, Yu J, Martin KA. Sci Signal. 2015 May 12;8(376):ra44.
Epigenetic regulation of smooth muscle cell plasticity.
Liu R, Leslie KL, Martin KA. Biochim Biophys Acta. 2015 Apr;1849(4):448-53
Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, Wu CL, Sano S, Muralidharan S, Rius C, Vuong J, Jacob S, Muralidhar V, Robertson AA, Cooper MA, Andrés V, Hirschi KK, Martin KA, Walsh K. Science. 2017 Feb 24;355(6327):842-847. doi: 10.1126/science.aag1381.
Coordinating Regulation of Gene Expression in Cardiovascular Disease: Interactions between Chromatin Modifiers and Transcription Factors.
Front Cardiovasc Med. 2017 Apr 6;4:19. doi: 10.3389/fcvm.2017.00019. eCollection 2017.
Full List of PubMed Publications
- Jin Y, Xie Y, Ostriker AC, Zhang X, Liu R, Lee MY, Leslie KL, Tang W, Du J, Lee SH, Wang Y, Sessa WC, Hwa J, Yu J, Martin KA: Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response. Arterioscler Thromb Vasc Biol. 2017 Dec; 2017 Oct 12. PMID: 29025710
- Sizer AJ, Martin KA: Respecting boundaries: CTCF, chromatin structural organization, and heart failure. J Thorac Dis. 2017 Dec. PMID: 29312684
- Bauer AJ, Martin KA: Coordinating Regulation of Gene Expression in Cardiovascular Disease: Interactions between Chromatin Modifiers and Transcription Factors. Front Cardiovasc Med. 2017; 2017 Apr 6. PMID: 28428957
- Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, Wu CL, Sano S, Muralidharan S, Rius C, Vuong J, Jacob S, Muralidhar V, Robertson AA, Cooper MA, Andrés V, Hirschi KK, Martin KA, Walsh K: Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017 Feb 24; 2017 Jan 19. PMID: 28104796
- Liu R, Bauer AJ, Martin KA: A New Editor of Smooth Muscle Phenotype. Circ Res. 2016 Jul 22. PMID: 27458192
- Lee SH, Du J, Stitham J, Atteya G, Lee S, Xiang Y, Wang D, Jin Y, Leslie KL, Spollett G, Srivastava A, Mannam P, Ostriker A, Martin KA, Tang WH, Hwa J: Inducing mitophagy in diabetic platelets protects against severe oxidative stress. EMBO Mol Med. 2016 Jul; 2016 Jul 1. PMID: 27221050
- Ostriker AC, Martin KA: Bromodomain Blockade for Intimal Hyperplasia--A Good BET? EBioMedicine. 2015 Nov; 2015 Nov 10. PMID: 26870770
- Ostriker AC, Martin KA: Bromodomain Blockade for Intimal Hyperplasia - A Good BET? EBioMedicine. 2015 Nov; 2015 Nov 10. PMID: 28958493
- Martin KA, Mani MV, Mani A: New targets to treat obesity and the metabolic syndrome. Eur J Pharmacol. 2015 Sep 15; 2015 May 19. PMID: 26001373
- Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WH, Lee SH, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA, Hwa J: Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood. 2015 May 28; 2015 Mar 26. PMID: 25814526
- Xie Y, Jin Y, Merenick BL, Ding M, Fetalvero KM, Wagner RJ, Mai A, Gleim S, Tucker DF, Birnbaum MJ, Ballif BA, Luciano AK, Sessa WC, Rzucidlo EM, Powell RJ, Hou L, Zhao H, Hwa J, Yu J, Martin KA: Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition. Sci Signal. 2015 May 12; 2015 May 12. PMID: 25969542
- Liu R, Leslie KL, Martin KA: Epigenetic regulation of smooth muscle cell plasticity. Biochim Biophys Acta. 2015 Apr; 2014 Jun 15. PMID: 24937434
- Martin KA, Hirschi KK: The magic touch: endothelial cells muscle-up adipose. Circ Res. 2014 Oct 10. PMID: 25301822
- Liu R, Jin Y, Tang W, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA: Response to letter regarding article, "ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity". Circulation. 2014 Aug 19. PMID: 25135133
- Thompson AM, Martin KA, Rzucidlo EM: Resveratrol induces vascular smooth muscle cell differentiation through stimulation of SirT1 and AMPK. PLoS One. 2014; 2014 Jan 8. PMID: 24416418
- Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA: Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation. 2013 Oct 29; 2013 Sep 27. PMID: 24077167
- Gleim S, Stitham J, Tang WH, Li H, Douville K, Chelikani P, Rade JJ, Martin KA, Hwa J: Human thromboxane A2 receptor genetic variants: in silico, in vitro and "in platelet" analysis. PLoS One. 2013; 2013 Jun 28. PMID: 23840660
- Jaba IM, Zhuang ZW, Li N, Jiang Y, Martin KA, Sinusas AJ, Papademetris X, Simons M, Sessa WC, Young LH, Tirziu D: NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. J Clin Invest. 2013 Apr. PMID: 23454748
- Ge X, Ren Y, Bartulos O, Lee MY, Yue Z, Kim KY, Li W, Amos PJ, Bozkulak EC, Iyer A, Zheng W, Zhao H, Martin KA, Kotton DN, Tellides G, Park IH, Yue L, Qyang Y: Modeling supravalvular aortic stenosis syndrome with human induced pluripotent stem cells. Circulation. 2012 Oct 2; 2012 Aug 22. PMID: 22914687
- Gleim S, Stitham J, Tang WH, Martin KA, Hwa J: An eicosanoid-centric view of atherothrombotic risk factors. Cell Mol Life Sci. 2012 Oct; 2012 Apr 11. PMID: 22491820
- Tang WH, Martin KA, Hwa J: Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol. 2012; 2012 May 9. PMID: 22582044
- Ding M, Rzucidlo EM, Davey JC, Xie Y, Liu R, Jin Y, Stavola L, Martin KA: Adiponectin in the heart and vascular system. Vitam Horm. 2012. PMID: 23017720
- Stitham J, Midgett C, Martin KA, Hwa J: Prostacyclin: an inflammatory paradox. Front Pharmacol. 2011; 2011 May 13. PMID: 21687516