Oxidants and Nitric Oxide in Coronary Vascular Function

New York Medical College, Valhalla NY

Investigators

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Abstract

The central hypothesis of this project is that specific mechanisms regulating changes in NAD(P)H oxidase[unreadable] (Nox) activity and subunit expression have important roles, in controlling aspects of mediator release from[unreadable] endothelium and signaling mechanisms observed to control vascular smooth muscle contractile function[unreadable] through both changes in ROS and redox control mechanisms. Studies in Aim 1 will define the influence of[unreadable] pathways of Nox oxidase regulation by interactions between Ang II, stretch, a stimuli of protein kinase C[unreadable] (PKC), and altered availability of NAD(P)H on ROS and redox regulation of vascular contractile function in[unreadable] the absence of vascular disease or endothelial factors. The focus of the systems studied include the control[unreadable] of cytosolic NAD(P)H redox and glutathione redox, mitochondria! function (associated with energy[unreadable] metabolism, oxidant production and redox control), and the impact of these systems on specific ROS and[unreadable] redox-controlled signaling mechanisms known to regulate vascular force generation. Studies in Aim 2[unreadable] examine how changes in Nox activity control endothelial release of NO, ROS and reactive NO-derived[unreadable] species (RNS), and the influence of endothelium and NO-donor drug derived RNS on the systems studied in[unreadable] Aim 1. Emphasis will be placed on building on our previous signaling studies in bovine coronary arteries and[unreadable] extending these studies into mouse aortas due to the availability of mice deficient in the p47phox and Nox-2[unreadable] (gp91phox) subunits of Nox oxidases. Freshly isolated vascular smooth muscle cells will be studied by[unreadable] fluorescence imaging in the absence and presence of NO-donors to examine relationships between[unreadable] alterations in Nox activation with the detection of changes in ROS and cytosolic and mitochondria! NAD(P)H[unreadable] redox, and indicators of mitochondrial membrane potential and intra-mitochondrial superoxide. A focus of[unreadable] these studies is to develop an understanding processes that control interactions between cytosolic and[unreadable] mitochondrial NAD(P)H redox and ROS generation that are related to the control of vascular force[unreadable] generation. The studies in Aim 3 examine how many of the mechanisms studied in Aim 1 and Aim 2 are[unreadable] altered in vascular tissue derived from animals studied in the other projects exposed to acute and chronic[unreadable] increases in angiotensin II without increased blood pressure, in vivo to alterations in pressure, diabetics and[unreadable] aging.[unreadable]