ARRA: A Novel Mechanism by Which iPLA2 Links Diabetes to Cardiovascular Diseases

Grants and Contracts Details


iPLA2 is a member of the phospholipase A2 superfamily. iPLA2 is expressed in vascular smooth muscle cells (VSMC) and is implicated in signaling in smooth muscle contraction. Interestingly, iPLA2 is activated in cultured VSMC by high glucose and in the vessel wall by type 2 diabetes. Moreover, iPLA2 is required for reactive oxygen species (ROS) production by NAD(P)H oxidase in VSMC and tissues. In our NHLBI research grant aim 1, we proposed to use two independent approaches (1. DHE staining, 2. lucigenin-mediated enhanced chemiluminescence) to determine if iPLA2 is required for ROS production by NAD(P)H oxidase in diabetic vasculature. Those methods are widely-used in ROS detection, but there are some pitfalls associated with each method. Recently, a quantitative and sensitive HPLC-based assay has been developed and recognized as one of the "gold standard" methods to detect ROS in intact cells and tissues. We have set up this "gold standard" method in our lab. HPLC-based assay, in complementary with DHE and lucigenin-enhanced chemiluminescence methods, will resolve some intrinsic weaknesses associated with individual method, and significantly improve our ability to achieve the goal in our NHLBI research grant. Therefore, in aim 1, we propose to use HPLC to determine if iPLA2 is required for type 2 diabetes-induced ROS production by NAD(P)H oxidase in vascular smooth muscle tissues. In our NHLBI research grant aim 3, we proposed to use radiotelemetry to measure blood pressure in conscious type 2 diabetic mice to determine the in vivo significance of iPLA2 in type 2 diabetes-associated hypertension. Recently, we were intrigued by a recent publication (Nature Medicine 14, 64 - 68 (2008)) showing that radiotelemetry can also be used in anesthetized mice to determine pressor response. We have set up the radiotelemetry method in our lab so that we should be readily able to perform the similar study. Results from this in vivo study will allow better determining if iPLA2 is involved in smooth muscle hypercontractility in type 2 diabetes-associated hypertension. Therefore, in our aim 2, we propose to use radiotelemetry to determine if iPLA2 plays a causal role in pressor response increase in type 2 diabetic mice.
Effective start/end date7/15/096/30/12


  • National Heart Lung and Blood Institute: $258,056.00


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