Advance-CTR Pilot Projects Program (2016)
"Mitochondrial ROS-Dependent Modification of RyR/BKCa Signaling Axis in Diabetes"
Co-PI: Neel Sodha, MD
The project will explore whether alterations of specific proteins involved in vasodilation are altered in the diabetic vasculature. The ryanodine receptor (RyR) releases calcium in microdomains to activate the large conductance Ca++-activated K+ channel (BKCa), which when open causes vascular smooth muscle cells to hyperpolarize and subsequently relax. Reduced BKCa channel activation in diabetes in response to vasodilators has been described by multiple groups. In addition, we have preliminary data that oxidation of the RyR causes reduced Ca++ release to BKCa channels. Furthermore, increased oxidant stress is also present in diabetes. Therefore, in this proposal we will test the hypothesis that increased oxidant stress causes modifications to the RyR which limit BKCa-induced vasodilation. In the first aim we will determine if our hypothesis is correct by collecting mammary arteries discarded from non-diabetic and diabetic patients undergoing cardiopulmonary bypass surgery. Vascular smooth muscle responsiveness to the nitric oxide donor SNP will be evaluated in ex vivo vascular ring assays, and this response correlated to the levels of RyR oxidation, RyR and BKCa channel expression, and indices of diabetes (HbA1c etc..). We anticipate finding increased RyR oxidation in diabetics that will associate with reduced responsiveness to SNP. In the second aim, we will use control and diabetic mice and determine if in vivo treatment with a mitochondrial ROS scavenger or a BKCa channel activator can alleviate reduced vascular responsiveness and if this is associated with reduced RyR oxidation.