Abstract 542: Upregulation of Cyr 61 Expression in Atherosclerosis Is Mediated by β3 Integrins
Objective: Cyr 61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions, stimulates proliferation of cultured smooth muscle cells (SMC) and is upregulated by angiotensin II (Ang II). We studied whether Ang II inhibition decreased expression of Cyr 61 in atheromas of ApoE–/– mice with unilateral partial renal artery ligation (RAL).
Methods and Results: 18 week old ApoE–/– mice were randomized to unilateral RAL, RAL + treatment with irbesartan, RAL + treatment with aliskiren or sham-surgery for 90 days. RAL reduced blood flow (60 ± 6% of baseline values), resulted in a sustained increase in renin mRNA levels in the ligated kidney, and elicited a mild, sustained increase in systolic blood pressure (11% increase in weighted average of blood pressure) compared to sham-surgery. Treatment with irbesartan or aliskiren prevented the hypertensive response. Lipid deposition, measured by Oil-red O staining 90 days after surgery, was increased approximately 3 fold following RAL in both the aortic arch and in the descending aorta compared to sham-surgery. Treatment with irbesartan or aliskiren reduced the aortic arch and descending aorta lipid deposition to a level that was statistically similar to sham-surgery. Atheromas in the abdominal aorta showed intense staining for Cyr 61 in RAL mice but patchy, diffuse and less intense staining in RAL + irbesartan (43% less staining) and RAL + aliskiren (60% less staining) mice. Studies in RASMC showed that Cyr 61 was secreted in response to treatment with Ang II and that echistatin, a function-blocking disintegrin that binds αvβ3 integrins on SMC, reduced Cyr 61 induced proliferation of RASMC. In mice with RAL, atheromas showed generalized and intense staining for β3 integrins that co-localized with Cyr 61. In contrast, β3 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 Cyr 61 and β3 integrins.
Conclusions: Unilateral RAL resulted in a marked increase in Cyr 61 and β3 integrin expression within atheromas. Treatment with irbesartan or aliskiren significantly reduced aortic lipid deposition, and expression of Cyr 61 and β3 integrins in atheromas.
- © 2012 by American Heart Association, Inc.