Cocaine Exposure Increases Blood Pressure and Aortic Stiffness via the miR-30c-5p–Malic Enzyme 1–Reactive Oxygen Species Pathway. Issue 4 (April 2018) - Zhu, Wei
Abstract : Cocaine abuse increases the risk of cardiovascular 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 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 Me1 (malic enzyme 1), 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 (untranslated region). Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in smooth muscle cells resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in blood pressure 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 cardiovascular disease. Abstract : Supplemental Digital Content is available in the text.