My study was to pursue the better understanding the molecular mechanism of vascular disease like atherosclerosis and its treatment. When I was a postdoctoral fellow, I discovered the important role of p53 and ERK5 SUMOylation on regulating disturbed flow-mediated endothelial cell (EC) dysfunction via downregulation of SENP2, which is a SUMO-specific protease. This study provided a mechanistic framework to the well-accepted observation that disturbed flow induces endothelial dysfunction and accelerating atherosclerosis formation. Recently, I have started to determine the mechanism of atherosclerosis formation, especially vulnerable plaque formation in the advanced lesions focusing on the monocyte/macrophage biology. I found the possible involvement of macrophage ERK5 in this process and genetic deletion of ERK5 in the macrophage showed an increase in necrotic core and atherosclerosis formation via defective phagocytic clearance (efferocytosis), which has been shown an important role in vulnerable plaque formation. I hope that this study will reveal new insight into ERK5 regulation in macrophages in advanced lesion of atherosclerosis to find a novel therapeutic target.

• Le NT, Heo KS, Takei Y, Lee H, Woo CH, Chang E, McClain C, Hurley C, Wang X, Li F, Xu H, Morrell C, Sullivan MA, Cohen MS, Serafimova IM, Taunton J, Fujiwara K, Abe J. A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis. Circulation. 2013 Jan 29; 127(4):486-99.
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• Heo KS, Chang E, Takei Y, Le NT, Woo CH, Sullivan MA, Morrell C, Fujiwara K, Abe J. Phosphorylation of Protein Inhibitor of Activated STAT1 (PIAS1) by MAPK-Activated Protein Kinase-2 Inhibits Endothelial Inflammation via Increasing Both PIAS1 Transrepression and SUMO E3 Ligase Activity. Arterioscler Thromb Vasc Biol. 2013 Feb; 33(2):321-9.
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• Heo KS, Fujiwara K, Abe J. Glucagon-like Peptide-1 and its cardiovascular effects. Curr Atheroscler Rep. 2012 Oct; 14(5):422-8.
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• Lim JH, Jono H, Komatsu K, Woo CH, Lee J, Miyata M, Matsuno T, Xu X, Huang Y, Zhang W, Park SH, Kim YI, Choi YD, Shen H, Heo KS, Xu H, Bourne P, Koga T, Xu H, Yan C, Wang B, Chen LF, Feng XH, Li JD. CYLD negatively regulates transforming growth factor-ß-signalling via deubiquitinating Akt. Nat Commun. 2012; 3:771.
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• Le NT, Takei Y, Shishido T, Woo CH, Chang E, Heo KS, Lee H, Lu Y, Morrell C, Oikawa M, McClain C, Wang X, Tournier C, Molina CA, Taunton J, Yan C, Fujiwara K, Patterson C, Yang J, Abe J. p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction. Circ Res. 2012 Feb 17; 110(4):536-50.
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• Heo KS, Fujiwara K, Abe J. Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction. Circ J. 2011 Nov 25; 75(12):2722-30.
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• Heo KS, Lee H, Nigro P, Thomas T, Le NT, Chang E, McClain C, Reinhart-King CA, King MR, Berk BC, Fujiwara K, Woo CH, Abe J. PKC? mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. J Cell Biol. 2011 May 30; 193(5):867-84.
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• Chang E, Heo KS, Woo CH, Lee H, Le NT, Thomas TN, Fujiwara K, Abe J. MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation. Blood. 2011 Feb 24; 117(8):2527-37.
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• Woo CH, Le NT, Shishido T, Chang E, Lee H, Heo KS, Mickelsen DM, Lu Y, McClain C, Spangenberg T, Yan C, Molina CA, Yang J, Patterson C, Abe J. Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor. FASEB J. 2010 Dec; 24(12):4917-28.
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• Nigro P, Abe J, Woo CH, Satoh K, McClain C, O'Dell MR, Lee H, Lim JH, Li JD, Heo KS, Fujiwara K, Berk BC. PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5. Blood. 2010 Sep 16; 116(11):1971-9.
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• Heo KS, Kim DU, Kim L, Nam M, Baek ST, Park SK, Park Y, Myung CS, Hwang SO, Hoe KL. Activation of PKCbeta(II) and PKCtheta is essential for LDL-induced cell proliferation of human aortic smooth muscle cells via Gi-mediated Erk1/2 activation and Egr-1 upregulation. Biochem Biophys Res Commun. 2008 Mar 28; 368(1):126-31.
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