Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is relatively common in elderly patients with atherosclerosis. MURC (muscle-restricted coiled-coil protein)/Cavin-4 modulating the caveolae function of muscle cells is expressed in cardiomyocytes, skeletal muscle cells and smooth muscle cells. Here, we show a novel functional role of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and AAA development. Both wild-type (WT) and MURC/Cavin-4 knockout (MURC^-/-) mice subjected to periaortic application of CaCl₂ developed AAAs. Six weeks after CaCl₂ treatment, internal and external aortic diameters were significantly increased in MURC^-/- AAAs compared with WT AAAs, which were accompanied by advanced fibrosis in the tunica media of MURC^-/- AAAs. The activity of JNK and matrix metalloproteinase (MMP) -2 and -9 were increased in MURC^-/- AAAs compared with WT AAAs at 5 days after CaCl₂ treatment. At 6 weeks after CaCl₂ treatment, MURC^-/- AAAs exhibited attenuated JNK activity compared with WT AAAs. There was no difference in the activity of MMP-2 or -9 between saline and CaCl₂ treatments. In MURC/Cavin-4-knockdown VSMCs, TNFα-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, MURC^-/-, apolipoprotein E^-/- (ApoE^-/-), and MURC/Cavin-4 and ApoE double-knockout (MURC^-/-ApoE^-/-) mice were subjected to angiotensin II (Ang II) infusion. In both ApoE^-/- and MURC^-/-ApoE^-/- mice infused for 4 weeks with Ang II, AAAs were promoted. The internal aortic diameter was significantly increased in Ang II-infused MURC^-/-ApoE^-/- mice compared with Ang II-infused ApoE^-/- mice. In MURC/Cavin-4-knockdown VSMCs, Ang II-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Our results suggest that MURC/Cavin-4 in VSMCs modulates AAA progression at the early stage via the activation of JNK and MMP-9. MURC/Cavin-4 is a potential therapeutic target against AAA progression. Copyright © 2017 Elsevier Inc. All rights reserved.

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