Vishwesh Mokashi: Low Density Lipoprotein Receptor-Related Protein Initiates Angiotnesin II-Induced Abdominal Aortic Aneurysms

10. Project summary (must be completed on this page): Infusion of angiotensin II (Angll) into hyperlipidemic mice causes rapid formation of abdominal aortic aneurysms (AAAs) , allowing the study of mechanisms underlying their formation. Similar to human disease, Angll-induced AAA pathology in mice is characterized by extracellular matrix (ECM) degradation and macrophage accumulation in the media of the aorta. Smooth muscle cell (SMC) specific deficiency of low density lipoprotein receptor-related protein 1 (LRP) develop AAAs similar to the ones produced by Angll infusion in hyperlipidemic mice. LRP is an important regulator of all classes of proteases, especially matrix metalloproteinases-2 (MMP-2) and is involved in its endocytic clearance. SMCs are the primary source of MMP-2 and its expression and activity is increased in SMCs present in aneurysmal tissue. MMP-2 is also involved in the degradation of ECM components, such as elastin and type IV collagen. The degradation of elastin and type IV collagen releases peptides, which are known to promote monocyte chemotaxis, an initiating event in AAA formation. Preliminary in vivo and ex vivo studies demonstrate that Angll downregulates LRP protein levels in abdominal but not thoracic aortic tissue. This region-specific effect is also seen with cultured aortic SMCs. The mechanism and the functional role of the Angll-mediated LRP regulation and its involvement in AAAs is not apparent. Since the only cell type present in the aortic media prior to development of AAAs is the SMC, it is likely that this cell type provides the stimulus for ECM degradation and inflammatory cell recruitment during AAA initiation. Based on the above observations, this proposal tests the central hypothesis that, Angll-mediated downregulation of LRP in abdominal SMCs enhances MMP-2 mediated degradation of the ECM, thereby promoting monocyte chemotaxis. To test this hypothesis, the following aims are proposed: 1. Determine if Angll-mediated downregulation of LRP in cultured abdominal aortic SMCs enhances the synthesis and activation of MMP-2. 2. Determine if the Angll-mediated downregulation of LRP in cultured abdominal SMCs enhances proteolysis of elastin and type IV collagen. 3. To determine if Angll-mediated region-specific downregulation of LRP in cultured abdominal SMCs increases chemotaxis of monocytes.