Fellowship Calderon: The role calcium-independent phospholipase A2-and microRNA-1 in Angll-induced vascular remodeling and inflammation.

SPECIFIC AIMS Angiotensin II (AngIl) is critical for maintaining physiological cardiovascular homeostasis, Moreover, a large body of evidence indicates a pivotal role of Angll dysregulation in various cardiovascular pathologies including hypertension, arterial remodeling and inflammation. While tremendous progress has been made recently, the molecular mechanisms by which Angil contiibutes to the pathophysiology of hypertension, arterial remodeling and inflammation remain incompletely understood. Recent studies implicate an essential role of calcium-independent phospholipase A2 (IPLA2) in some of the Angil effects. Our preliminary studies show that genetic knockout iPLA2 abolishes Angli-induced 3H- thymidine incorporation, 3H-leucine incorporation, and mRNA increases of proinflamrnatory cytokine IL-S and chemokines MCP-1 in primary cultured vascular smooth muscle cells (VSMCs). These results demonstrate that iPLA2 is required in AnglI-induced VSMCs proliferation, hypertrophy and inflammation which are important cellular processes in various vascular pathologies. However, two important questions remain to be addressed. First, what are the molecular mechanisms by which iPLA2 mediates AnglI regulation of vascular smooth muscle cell functions? Secondly, in vivo, does iPLA2 play a critical role in Angil induced hypertension, vascular remodeling, and inflammation? To address these two specific questions, we hypothesize that 1PLA2 mediates Angil regulation of VSMCs proliferation, hypertrophy and cytokine synthesis in a microRNA-1 (miR-1) dependent manner and thus, is critical in AnglI induced increase in blood pressure, vascular remodeling and inflammation. I have constructed three specific aims to investigate the role of iPLA2 in regulating VSMCs functions at the cellular level and the correlation to an in vivo setting using iPLA2 knockout (iPLA2-Ko) and iPLA2 transgenic (iPLA2-Tg) mouse models. Both the iPLA2- Ko and iPLA2-Tg mouse models are currently available in our laboratory.