AngII Promotes Proinflammatory processes in Atherogenesis

There is evolving evidence for an important role of angiotensin II (AngII) in the atherogenic process. Data derived from clinical trials and animal models using ACE inhibitors indirectly suggests a role for AngII in the atherogenic process; however, the demonstration of a direct role of AngII in atherosclerosis is still lacking. Preliminary results demonstrate that chronic infusion of AngII promotes rapid development of atherosclerotic lesions and the striking formation of aneurysms in two mouse models of atherogenesis. The central hypothesis of the proposed studies is that AngII interacts with AT1 receptors on macrophages to augment atherogenesis and aneurysm formation by stimulating MCP-1 elaboration and potentiating macrophage and lymphocyte recruitment. To test this hypothesis the PI proposes the following specific aims: 1. Determine the specific AngII receptor responsible for the enhanced atherogenesis and formation of aneurysms using specific antagonists for AT1 or AT2 receptors. 2. Determine the combined effects of hyperlipidemia and AngII on the expression of AngII receptors. This will be defined in vivo and in vitro. Quantitative autoradiography will define the expression of distinct AngII receptors in arterial tissue during the evolution of atherosclerotic lesions and aortic aneurysms. These studies will be complemented by studies in cultured macrophages to determine the effects of hyperlipidemia and AngII on the regulation of AngII receptors. To link receptor changes to the central working hypothesis, the effect of AngII to release MCP-1 will be determined in vitro in cultured macrophages exposed to hyperlipidemic environments. 3. Determine the macrophage specific contribution of AngII receptor stimulation on the evolution of vascular diseases. This will be achieved by creating chimeric mice in which bone marrow transplantation will be performed to achieve a myeloid cell specific depletion of specific AngII in atherosclerosis susceptible strains. 4. Define the role of MCP-1 in AngII induced atherogenesis and formation of aneurysms. The contribution of AngII induced MCP-1 release to atherogenesis and aneurysm formation will be defined in vivo using mice that are unable to secrete MCP-1 or unable to respond to this cytokine because of deletion of its major receptor, CCR-2. These studies will define mechanisms for AngII augmentation of atherogenesis. Moreover, the development of this animal model for aortic aneurysm formation will allow for definition of mechanisms contributing to this vascular pathology.