Abstract 17070: The Renin-angiotensin System Regulates Expression of Cyr61 and β3 Integrins in Atheroma in ApoE–/– Mice With Unilateral Renal Artery Ligation

Introduction: Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions, stimulates growth responses of cultured smooth muscle cells (SMC) and is upregulated by angiotensin II (Ang II). Hypothesis: Determine whether Cyr61 is expressed in atheroma from ApoE –/– mice with unilateral renal artery ligation. Methods and Results: 18 week old ApoE –/– mice were randomized to unilateral renal artery ligation (RAL), RAL + treatment with irbesartan, RAL + treatment with aliskiren or sham-surgery for 90 days. RAL reduced blood flow (60 ± 6% of baseline values), increased renin mRNA levels in the ligated kidney, and elicited a mild, sustained increase in systolic blood pressure compared to sham-surgery. Lipid deposition, measured by Oil-red O staining, was increased approximately 3 fold in the aortic arch and 2 fold in the descending aorta in the RAL group compared to sham-surgery. Treatment with irbesartan or aliskiren prevented the hypertensive response and reduced descending aorta lipid deposition to a level that was statistically similar to sham-surgery. Aliskiren, but not irbesartan, prevented the increase in aortic arch lipid deposition. Atheromas in the abdominal aorta showed intense staining for Cyr61 in RAL mice but patchy, diffuse and less intense staining in RAL + irbesartan (43% less staining) and RAL + aliskiren (60% less staining) mice. Atheromas showed generalized and intense staining for β 3 integrins that co-localized with Cyr61 in mice with RAL. In contrast, β 3 integrin staining was localized, discrete and even non-existent in atheromas from RAL + irbesartan and RAL + aliskiren mice. Sham-surgery mice had no atheromas and minimal staining for Cyr61 and β 3 integrins. Studies in cultured rat aortic SMC showed that Cyr61 was secreted in response to treatment with Ang II and that echistatin, a function-blocking disintegrin that binds α v β 3 integrins on SMC, reduced Cyr61-induced proliferation, migration and signaling. Conclusions: Cyr61 and β 3 integrins are expressed in aortic atheroma from ApoE –/– mice with unilateral RAL and this expression is regulated by the renin-angiotensin system.