Current Research
1. microRNA biology During my postdoctoral training, we identified that miR-483 is an atheroprotective flow-induced miRNA. By collaborating with the Kawasaki Research Center at UCSD, I found that the endothelial to mesenchymal transition (endoMT) was induced in Kawasaki disease, causing inflammation in coronary arteries, because of an impaired KLF4-miR-483-CTGF pathway. Atorvastatin treatment improved endothelial function and prevented Kawasaki disease coronary artery aneurysms by targeting the endoMT. Unexpectedly, we found that miR-483 can target the PCSK9 3’UTR. MiR-483 administration significantly reduced total cholesterol and LDL-C levels in hyperlipidemic mouse models. Because miR-483 targets multiple pro-fibrotic and pro-inflammatory genes, inhalation of a lentivirus overexpressing miR-483 ameliorated pulmonary hypertension in rodents. Publications of the related findings are listed below:
a. He M, Chen Z, Martin M, Zhang J, Sangwung P, Woo B, Tremoulet AH, Shimizu C, Jain MK, Burns JC, Shyy JY. miR-483 Targeting of CTGF Suppresses Endothelial-to-Mesenchymal Transition: Therapeutic Implications in Kawasaki Disease. Circ Res. 2017; 120(2):354-365.
b. Dong J, He M, Li J, Pessentheiner A, Wang C, Zhang J, Sun Y, Wang W-T, Zhang Y, Liu J, Wang S-C, Huang P-H, Gordts PL, Yuan Z-Y, Tsimikas S, John Yj Shyy JY. MicroRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production. JCI Insight. 2020;5(23):e143812. (Co-first author)
c. Zhang J, He Y, Yan X, Chen S, He M, Lei Y, Zhang J, Gongol B, Gu M, Miao Y, Bai L, Cui X, Wang X, Zhang Y, Fan F, Li Z, Shen Y, Chou C-H, Huang H-D, Malhotra A, Rabinovitch M, Jing Z-C, Shyy JY. MicroRNA-483 amelioration of experimental pulmonary hypertension. EMBO Mol Med. 2020;12(5):e11303.
2. Vascular biology under aging-related vascular diseases Ever since my master’s degree, I’ve been interested in multiple aging-accelerated vascular diseases (e.g., atherosclerosis, rheumatoid arthritis, diabetes, and gout). During my master’s degree, we identified NF-kB activation in peripheral blood mononuclear cells and enhanced serum concentrations of pro-inflammatory cytokines in type 2 diabetic patients. Early in 2013, we found that MCPIP detrimentally inhibited PI3K-Akt–induced endothelial nitric oxide (NO) synthase phosphorylation and NO bioavailability in a collagen-induced arthritis mouse model and rheumatoid arthritis patients. I also identified the SREBP2 transactivation of YAP involved in gout-induced endothelial impairment. Publications of the related findings and data are listed below.
a. He L, He M, Lv X, Pu D, Su P, Liu Z. NF-kappaB binding activity and pro-inflammatory cytokines expression correlate with body mass index but not glycosylated hemoglobin in Chinese population. Diabetes Res. Clin. Pract. 2010; 90(1):73-80.
b. He M, Liang X, He L, Wen W, Zhao S, Wen L, Liu Y, Shyy JY, Yuan Z. Endothelial dysfunction in rheumatoid arthritis: the role of monocyte chemotactic protein-1-induced protein. Arterioscler Thromb Vasc Biol. 2013; 33(6):1384-91.
c. Zhao Z, Zhao Y, Zhang Y, Shi W, Li X, Shyy J, He M, Wang L. Gout-Induced Endothelial Impairment: The Role of SREBP2 Transactivation of YAP. FASEB J. 2021;35(6):e21613. (Corresponding author)
3. Shear stress regulates EC function and atherogenesis To identify novel mechanisms in shear stress-regulated endothelial functions and atherogenesis, we integrated RNA-seq; ATAC-seq; H3K27ac, H3K4me3, H3K4me1 histone ChIP-seq; and RRBS-seq data to dissect the epigenetic regulations in endothelial cells under different flow patterns. KLF4 was identified as the shear stress–induced master transcription factor that regulates many pulsatile shear stress-inducible genes via both transcriptional and epigenetic regulation. We found that 1) ITPR3, a calcium channel on the ER membrane, was regulated by KLF4 via modification of histone codes and chromatin accessibility; also, a set of flow-regulated novel genes were identified from this newly developed approach; 2) CH25H, induced by PS-KLF4 pathway epigenetically, contributes to LXR expression and mitigates atherosclerosis susceptibility; 3) atheroprone flow enhances the endoMT in vitro and in vivo; and 4) IP3R1, a PS-upregulated calcium channel in ECs, is atheroprotective. Publications of the related findings and data are listed below.
a. He M, Huang TS, Li S, Hong HC, Chen Z, Martin M, Zhou X, Huang HY, Su SH, Zhang J, Wang WT, Kang J, Huang HD, Zhang J, Chien S, Shyy JY. Atheroprotective Flow Upregulates ITPR3 (Inositol 1,4,5-Trisphosphate Receptor 3) in Vascular Endothelium via KLF4 (Krüppel-Like Factor 4)-Mediated Histone Modifications. Arterioscler Thromb Vasc Biol. 2019; 39(5):902-914.
b. Li Z, Martin M, Zhang J, Huang HY, Bai L, Zhang J, Kang J, He M, Li J, Maurya MR, Gupta S, Zhou G, Sangwung P, Xu YJ, Lei T, Huang HD, Jain M, Jain MK, Subramaniam S, Shyy JY. Krüppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility. Circulation. 2017; 136(14):1315-1330.
c. Dong Y, Lee Y, Cui K, He M, Wang B, Bhattacharjee S, Zhu B, Yago T, Zhang K, Deng L, Ouyang K, Wen A, Cowan DB, Song K, Yu L, Brophy ML, Liu X, Wylie-Sears J, Wu H, Wong S, Cui G, Kawashima Y, Matsumoto H, Kodera Y, Wojcikiewicz RJH, Srivastava S, Bischoff J, Wang D-Z, Ley K, Chen H. Epsin-mediated degradation of IP3R1 fuels atherosclerosis. Nat Commun. 2020;11(1):3984.
d. Lai B, Li Z, He M, Wang Y, Chen L, Zhang J, Yang Y, Shyy JY. Atheroprone flow enhances the endothelial-to-mesenchymal transition. Am. J. Physiol. Heart Circ. Physiol.2018; 315(5):H1293–H1303. (Co-first author)
