Fellowship for Venkateswaran Subramanian: Role of peroxisome proliferator activated receptor gamma in angiotensin II induced abdominal aortic aneurysm

Infusion of angiotensin II (Angll) into hyperlipidemic mice causes rapid formation of abdominal aortic aneurysm (AAA). Similar to human disease, Angll-induced AAA pathology in mice is characterized by extracellular matrix degradation and inflammation initiated by macrophage accumulation in the media of the aorta. Peroxisome proliferator-activated receptor y (PPARy) ligands, namely the insulin-sensitizing thiazolidinedione compound, is shown to attenuate Angll induced AAA (Jonathan Golledge, Personal Communication). PPARy, a nuclear transcription factor is expressed in various cell types including smooth muscle cells (SMC) and its ligands are in clinical use for the treatment of insulin resistance. Understanding the role of PPARy in AAA formation may identify a basis for drug therapy to target the aneurysm expansion. Angll infusion into hyperlipidemic mice is shown to be associated with decreased expression of PPARy in the aorta. Our preliminary studies show that Angll downregulates PPARy protein and gene expression in cultured mouse aortic SMCs through angiotensin II type 1 (AT1) receptors. Preliminary data also demonstrates a role for transforming growth factor beta1 (TGFb1) activation in Angll-mediated downregulation of PPARy in aortic SMCs. Overexpression of TGF-b1 has been observed in SMCs of human AAA tissues. Activation of PPARy by ligands abolishes the increased TGF-b signal in SMCs of hyperlipidemic mice with AAA. Taken together, these data suggest that Angll-mediated reduction in PPARy via TGF- 1 plays a role in the development of MA. However, the mechanism of Angll-mediated PPARy downregulation in SMCs via TGF-b1 and its involvement in AAA formation has not been determined. Since the aortic media contains only SMCs prior to development of AAAs, it is likely that this cell type provides the stimulus for AAA initiation. Based on the above background and preliminary findings, this proposal tests the central hypothesis that Angll induces AAA formation by downregulating PPARy in aortic SMCs via TGF-b1 dependent mechanism. To test this hypothesis, the following aims are proposed: Aim 1: Determine the contribution of SMC-specific PPARy to Angll-induced AAA formation. Aim 2: Determine the contribution of SMC-specific PPARy to TGF-b1 blockade mediated attenuation of Angllinduced AAA formation.