Endothelin Type a Receptor Mediates Endothelin-1-induced Upregulation of Nadph Oxidase Activity in Human Aortic Smooth Muscle Cells

Endothelin system plays an important role in the pathophysiology of cardiovascular diseases. Endothelin-1 (ET-1), the main effector of the system, regulates important physiological processes including vascular tonus, cellular growth and proliferation. In pathological conditions such as diabetes, hypertension, obesity and atherosclerosis, excessive ET-1 synthesis induces oxidative stress, inflammation, fibrosis, and cellular phenotypic alterations of the vascular resident cells and infiltrated immune cells. We design this study to investigate the molecular mechanisms whereby ET-1 induces reactive oxygen species (ROS) formation in human aortic smooth muscle cells (SMC). Lucigenin-enhanced chemiluminescence and dichlorofluorescin assays indicated that exposure of SMC to ET-1 up-regulates NADPH oxidases (Nox) activity and intracellular production of ROS in a dose-dependent manner. The chemical inhibition of endothelin receptor type A (ETA) receptor, but not endothelin receptor type B (ETB), significantly reduced the ET-1-induced Nox activity. Collectively, these evidence provide new mechanistically means by which ROS are generated in SMC in response to ET-1 stimulation. Pharmacological inhibition of ETA receptor may represent a reliable therapeutic strategy to reduce oxidative stress in cardiovascular pathologies.