Statins improve endothelial function via suppression of epigenetic-driven EndMT Nature Cardiovascular Research (2023). https://doi.org/10.1038/s44161-023-00267-1
Date
05/08/2023Abstract
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 SOX9 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.
Author List
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. WuAuthor
Chun Liu PhD Assistant Professor in the Physiology department at Medical College of WisconsinView Online
