Targeting miR-200c to Ameliorate Diabetes-Induced Endothelial Dysfunction

Endothelial dysfunction is one of the earliest manifestations of diabetes that can lead to numerous debilitating micro- and macrovascular complications (1,2). Identifying factors that mediate or augment endothelial dysfunction in diabetes can lead to the development of much-needed therapies that target early stages of various vascular complications and thereby prevent further progression. Chronic endothelial dysfunction includes impaired endothelium-dependent vasorelaxation (EDR), increased inflammation, and dysregulation of vascular remodeling (1–3). Inactivation or reduced bioavailability of gasotransmitter nitric oxide (NO), also known as EDR factor, is a key factor involved in the development of vascular diseases such as hypertension and atherosclerosis (1,4), which are accelerated under diabetic conditions. NO is produced by endothelial NO synthase (eNOS), and several studies have demonstrated increased oxidative stress, eNOS uncoupling, and reduced NO bioavailability under diabetic conditions (1–4). In addition to NO, endothelial cells (ECs) also produce several prostanoids with vasodilator and vasoconstrictor activities (5) mainly via the actions of the cyclooygenase enzymes COX-1 and COX-2. A fine balance between the levels of these prostanoids contributes to normal EDR. COX-2 produces both prostacyclin (PGI2), which reduces platelet aggregation, and prostaglandin E2 (PGE2), which can reduce EDR. In diabetes, high glucose (HG)-induced oxidative stress and reactive oxygen species (ROS) increase the expression of COX-2 and prostaglandin H2 (PGH2), a common precursor of prostaglandins. However, HG-induced ROS inhibit further metabolism of PGH2 into the vasodilator PGI2 via inhibition of PGI …