Cocaine Exposure Increases Blood Pressure and Aortic Stiffness via the miR-30c-5p—Me1—ROS Pathway

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 71; no. 4; pp. 752 - 760
• Main Authors: Zhu, Wei, Wang, Huilan, Wei, Jianqin, Sartor, Gregory C, Bao, Michelle Meiqi, Pierce, Clay T, Wahlestedt, Claes R, Dykxhoorn, Derek M, Dong, Chunming
• Format: Journal Article
• Language: English
• Published: 26.02.2018
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.117.10213

Cocaine abuse increases the risk of cardiovascular (CV) mortality and morbidity; however, the underlying molecular mechanisms remain elusive. By using a mouse model for cocaine abuse/use, we found that repeated cocaine injection led to increased blood pressure (BP) and aortic stiffness in mice associated with elevated levels of reactive oxygen species (ROS) in the aortas, a phenomenon similar to that observed in hypertensive humans. This ROS elevation was correlated with downregulation of malic enzyme 1 (Me1), an important redox molecule that counteracts ROS generation, and upregulation of microRNA (miR)-30c-5p that targets Me1 expression by directly binding to its 3’UTR. Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells (SMCs) recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in SMCs resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in BP and aortic stiffness—a similar effect to that produced by treatment with the antioxidant N-acetyl cysteine. Discovery of this novel cocaine-↑miR-30c-5p-↓Me1-↑ROS pathway provides a potential new therapeutic avenue for treatment of cocaine abuse-related CV disease.