Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice
Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice
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DOI：
10.1093/cvr/cvab179
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发表时间：
2021-07-12
影响因子：
10.8
通讯作者：
Ouchi, Noriyuki
中科院分区：
文献类型：
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作者：
Fang, Lixin;Ohashi, Koji;Ouchi, Noriyuki
腹主动脉瘤（AAA）是一种日益增加的威胁生命的疾病。肥胖会增加AAA的风险。Omentin是一种循环脂肪因子，在肥胖并发症中下调。在这里，我们研究了网膜素是否可以调节血管紧张素（Ang）II诱导的AAA形成载脂蛋白E基因敲除（apoE-KO）小鼠。方法和结果apoE-KO小鼠与脂肪组织中表达人网膜素基因的转基因小鼠（OMT-Tg小鼠）杂交，产生apoE-KO/OMT-Tg小鼠。apoE-KO/OMT-Tg和apoE-KO小鼠通过使用渗透微型泵进行连续的Ang II输注。与apoE-KO小鼠相比，apoE-KO/OMT-Tg小鼠AAA形成的发生率较低，AAA的最大直径减小。与apoE-KO小鼠相比，apoE-KO/OMT-Tg小鼠对Ang II的反应显示内侧弹性纤维的破坏减弱。与apoE-KO小鼠相比，apoE-KO/OMT-Tg小鼠还显示主动脉壁中基质金属蛋白酶（MMP）9、MMP 2和促炎基因的表达水平降低。此外，网膜素的全身给药也减弱了apoE-KO小鼠中响应于Ang II的AAA形成和内侧弹性纤维的破坏。用网膜蛋白处理人单核细胞衍生的巨噬细胞减弱了MMP 9和促炎介质的表达，以及脂多糖刺激后MMP 9的活化。在用肿瘤坏死因子α刺激后，用网膜蛋白处理人血管平滑肌细胞（VSMCs）可降低MMP 2的表达和活化。Omentin处理增加人巨噬细胞和VSMC中Akt的磷酸化水平。网膜素对MMP 9和MMP 2表达的抑制作用分别通过抑制巨噬细胞和VSMC中的整合素-α V β 3/PI 3-激酶/Akt信号传导而逆转。结论网膜素可能通过抑制MMP 9和MMP 2的表达及血管壁的炎症反应，抑制Ang II诱导的AAA的发生发展。
Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. Methods and results apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor alpha. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-alpha V beta 3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively. Conclusion These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.