Patients with metabolic syndrome (MS) have a significantly higher risk for coronary artery diseases and type-2 diabetes. MS is associated with vasomotor and endothelial dysfunction and the dys-regulation of coronary blood flow, which in turn could underlie increased cardiovascular morbidity and mortality. However, the precise mechanism responsible for MS-induced vascular endothelial dysfunction is still unknown. Although previous small animal studies and our preliminary data have shown that down-regulation of SKCa/IKCa may be responsible for MS-induced endothelial dysfunction, the signaling pathways responsible for MS-induced down-regulation of SKCa/IKCa have are far from clear. The goal of this project is to investigate how persistent oxidative stress (ROS) and PKC over-expression/activation during MS dys-regulates small (SKCa) and intermediate (IKCa) conductance of calcium-activated potassium channels of porcine coronary endothelial cells and arteriolar function. We hypothesize that persistent overproduction ROS via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and mitochondria and PKC during MS result in: 1) down-regulation of SKCa/IKCa-induced endothelium-dependent relaxation; 2) impairment of SKCa/IKCa-induced endothelium-dependent hyperpolarization and KCa current densities; 3) Inhibition of ROS, Nox and mROS and PKC may potentiate SKCa/IKCa opener-induced endothelial protection of the coronary arterioles of pigs with MS. Using a clinically relevant-MS model in pigs, in-vitro pig coronary arterioles and porcine coronary endothelial cells, we will test our hypothesis by completing three specific aims. Aim 1: We will study whether inhibition of ROS, Nox, mROS and PKC may affect SKCa/IKCa activator-mediated endothelium-dependent relaxation of coronary arterioles in the pigs with MS; Aim 2: We will investigate whether inhibition of ROS, NOX, mROS and PKC during MS may affect SKCa/IKCa channel activity, current density and endothelium-derived hyperpolerization of porcine coronary endothelial cells; Aim 3: We will study whether administration of oxygen-free radical scavengers or PKC inhibitors may potentiate exogenous KCa activators-induced relaxation and endothelial protection of in-vitro pig coronary arterioles against simulated cardioplegic I/R injury. This project will hopefully lead to novel drug therapies to preserve coronary endothelial function for patients with MS and ischemic heart diseases during cardiac surgery.
|Effective start/end date||07/01/2015 → 06/30/2018|