Abstract 13834: MURC/cavin-4 Aggravates Abdominal Aortic Aneurysm With JNK Overactivation in Vascular Smooth Muscle Cells
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. Mutations in MURC/Cavin-4 have been identified in patients with dilated cardiomyopathy. However, roles of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and the development of AAA remain unknown.
Methods and Results: To examine the role of MURC/Cavin-4 in AAA, we subjected wild-type (WT) and MURC/Cavin-4 knockout (MURC-/-) mice to a model of AAA induced by periaortic application of CaCl2. After six 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 JNK and MMP-2 activities were increased in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice at 5 days after treatment, whereas these activities were suppressed in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice at 6 weeks after treatment. To assess the role of MURC/Cavin-4 in VSMCs, we then examined JNK activity in MURC knocked-down VSMCs with or without TNFα treatment. Although there was no significant difference between MURC knocked-down VSMCs and control VSMCs in JNK phosphorylation under basal conditions, TNFα-induced JNK phosphorylation was overactivated in MURC knocked-down VSMCs compared with control VSMCs. Collagen 1 mRNA expression was also increased in MURC knocked-down VSMCs with TNFα treatment.
Conclusion: MURC/Cavin-4 deficiency deteriorates AAA with JNK overactivation at an early stage of AAA development. Our results suggest that MURC/Cavin-4 modulates AAA progression via JNK activation in VSMCs.
Author Disclosures: K. Miyagawa: None. T. Ogata: None. N. Nakanishi: None. T. Hamaoka: None. N. Maruyama: None. T. Kasahara: None. T. Ueyama: None.
- © 2014 by American Heart Association, Inc.