Abstract 15651: Genetic Deletion Of MURC/cavin-4 Aggravates Abdominal Aortic Aneurysm
Background: Abdominal aortic aneurysm (AAA) is a relatively common disease in the elderly population. MURC (muscle-restricted coiled-coil protein)/cavin-4, a fourth member of the cavin family which regulates caveolae function, is expressed in cardiomyocytes, smooth muscle cells, and skeletal myocytes. Deficiency of caveolin-1, a critical component of caveolae, has been to be protective against atherosclerosis. Although mutations in MURC have been identified in patients with dilated cardiomyopathy, roles of MURC in vascular smooth muscle cells (VSMCs) and the development of AAA remain unknown.
Methods and Results: To examine the role of MURC in AAA, we subjected wild-type (WT) and MURC knockout (MURC-/-) mice to a model of AAA induced by periaortic application of CaCl2. After 6 weeks of CaCl2 treatment, the internal aortic diameter assessed by ultrasonography was significantly increased in MURC-/- mice compared with WT mice. Measurement of the external aortic diameter after perfusion fixation also showed an increase in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice. Fibrosis and cell infiltration of the tunica media were increased in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice. The dilation of the aorta in CaCl2-treated MURC-/- mice was accompanied by disruption of the elastic lamellae. The activation of JNK was suppressed in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice. Since MURC is expressed only VSMCs in the aorta, we then examined the role of MURC in proliferation and migration of VSMCs. MURC-/- VSMCs showed suppression of fetal bovine serum (FCS)-induced proliferation and migration, which were accompanied by reduced RhoA activity. Furthermore, MURC knockdown in VSMCs suppressed TNF-α-induced JNK activation and FCS-induced proliferation and migration. Overexpression of MURC in VSMCs induced RhoA activation, proliferation, and migration in VSMCs. MURC-induced proliferation and migration were inhibited by a ROCK inhibitor.
Conclusion: MURC regulates VSMC proliferation and migration through the Rho/ROCK pathway. Deficiency of MURC deteriorates AAA accompanied by disruption of the elastic lamellae, which is likely attributable to reduced proliferation and migration of VSMCs.
- © 2013 by American Heart Association, Inc.