Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm
Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm
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DOI：
10.1016/j.bbrc.2017.04.096
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发表时间：
2017-06-03
影响因子：
3.1
通讯作者：
Matoba, Satoaki
中科院分区：
文献类型：
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作者：
Miyagawa, Kotaro;Ogata, Takehiro;Matoba, Satoaki
腹主动脉瘤（AAA）在老年动脉粥样硬化患者中相对常见。MURC（muscle-restricted coiled-coil protein）/Cavin-4调节肌细胞的小窝功能，在心肌细胞、骨骼肌细胞和平滑肌细胞中表达。在这里，我们展示了MURC/Cavin-4在血管平滑肌细胞（VSMCs）和AAA发展中的新功能作用。野生型（WT）和MURC/Cavin-4基因敲除（MURC-/-）小鼠经主动脉周围应用CaCl 2后均产生AAA。CaCl 2处理后6周，与WT AAA相比，MURC-/-AAA的主动脉内径和外径显著增加，并伴有MURC-/-AAA的图尼卡中膜的晚期纤维化。CaCl 2处理后第5天，MURC-/- AAAs中JNK和基质金属蛋白酶（MMP）-2和-9的活性与WT AAAs相比增加。在CaCl 2处理后6周，与WT AAA相比，MURC-/-AAA表现出减弱的JNK活性。生理盐水和CaCl_2处理的MMP-2和MMP-9活性无差异。在MURC/Cavin-4敲低的VSMCs中，与对照VSMCs相比，TNF α诱导的JNK和MMP-9活性增强。此外，对WT、载脂蛋白E-/-（ApoE（-/-））和MURC/Cavin-4和ApoE双敲除（MURC（-/-）ApoE（-/-））小鼠进行血管紧张素II（Ang II）输注。在ApoE（-/-）和MURC（-/-）ApoE（-/-）小鼠中，用Ang II输注4周，AAA均被促进。与Ang II灌注ApoE（-/-）小鼠相比，Ang II灌注MURC（-/-）ApoE（-/-）小鼠的主动脉内径显著增加。在MURC/Cavin-4敲低的VSMCs中，与对照VSMCs相比，Ang II诱导的JNK和MMP-9活性增强。我们的研究结果表明，VSMCs中的MURC/Cavin-4通过激活JNK和MMP-9在早期阶段调节AAA进展。MURC/Cavin-4是抗AAA进展的潜在治疗靶点。(C)2017爱思唯尔公司All rights reserved.
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, TNF alpha-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, 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. (C) 2017 Elsevier Inc. All rights reserved.