iPLA2 (calcium independent phospholipase A2) is a member of the phospholipase A2 superfamily that is expressed in vascular smooth muscle and exhibits diverse cellular functions. Our preliminary data show that iPLA2 is activated/up-regulated in the vasculature of type 2 diabetic db/db mice and high-fat diet-fed mice and by high glucose in primary cultured vascular smooth muscle cells (VSMC). Moreover, inhibition of iPLA2 by BEL, a pharmacological inhibitor, or genetic deletion abolishes, whereas overexpression of iPLA2 exacerbates high glucose-induced NAD(P)H oxidase-mediated superoxide production in cultured VSMCs. These data clearly show that iPLA2 is required for high glucose-induced NAD(P)H oxidase-mediated ROS production in cultured VSMCs and thus implicate an potentially important role of iPLA2 in the diabetes induced ROS increase in vascular wall. While the increased ROS may affect multiple cellular functions, our data show that CPI-17, a downstream player in RhoA/ROCK/PKC pathway, is regulated by ROS, suggesting that iPLA2 regulates RhoA/ROCK/CPI-17 pathway via ROS. Therefore, we hypothesize that type 2 diabetes activates iPLA2 in vascular smooth muscle, leading to enhanced NAD(P)H oxidase-mediated ROS production and consequent RhoA/ROCK/PKC/CPI-17 pathway activation, and thereby significantly contributes to type 2 diabetes- associated vascular smooth muscle hyper-contractility and hypertension.
Three Specific Aims are: 1) To test the hypothesis that iPLA2 is required for type 2 diabetes-induced ROS production by NAD(P)H oxidase in vascular smooth muscle tissues. 2) To test the hypothesis that iPLA2 is required for the type 2 diabetes- induced activation of RhoA/ROCK/CPI-17 via NAD(P)H oxidase in vascular smooth muscle tissue. 3) To determine the in vivo significance of iPLA2 in type 2 diabetes-associated vascular smooth muscle hyper- contractility and hypertension. Two type diabetic animal models (the high-fat diet-fed mice and db/db mice) in combination with the genetic modified mice (the iPLA2 transgenic, iPLA2 knockout, and p47phox deficient mice) will be used. The activities of iPLA2, NAD(P)H oxidase, and RhoA/ROCK/PKC/CPI-17 and vascular tone will be assayed in isolated vasculatures and blood pressure will be determined in animals by telemetry. While the development of hypertension in type 2 diabetes seems to be the result of multiple maladaptive pathways, results from the proposed studies will elucidate specific mechanisms that could lead to the identification of iPLA2 as a potential novel therapeutic target for the prevention and treatment of cardiovascular complications associated with type 2 diabetes.
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