From the Department of Physiology (J.L., Y.Z., A.D., H.L., M.C.G.).
Department of Pharmacology and Nutritional Sciences (S.L., T.H., Z.G.), University of Kentucky, Lexington.
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1063-1075. doi: 10.1161/ATVBAHA.117.310153. Epub 2018 Feb 8.
Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development.
SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone plus high salt intake and (2) angiotensin II infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by deoxycorticosterone acetate-salt, and deletion of BMAL1 in SMCs selectively upregulated TIMP4 (tissue inhibitor of metalloproteinase 4) and suppressed deoxycorticosterone acetate-salt-induced MMP (matrix metalloproteinase) activation and elastin breakages. Moreover, BMAL1 bound to the promoter and suppressed transcription.
These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion.
腹主动脉瘤（AAA）破裂时死亡率很高，但由于我们对其发病机制的了解有限，目前尚无有效的药物治疗 AAA。本研究探索了平滑肌细胞（SMC）BMAL1（脑和肌肉 ARNT 样蛋白-1）的新作用，该转录因子已知可调节昼夜节律，在 AAA 的发展中起作用。
SMC 中选择性敲除 BMAL1 可有效防止（1）MR（盐皮质激素受体）激动剂脱氧皮质酮乙酸盐或醛固酮加高盐摄入和（2）在高胆固醇血症小鼠中血管紧张素 II 输注引起的 AAA。脱氧皮质酮乙酸盐盐可上调主动脉 BMAL1，而 SMC 中 BMAL1 的缺失可选择性上调 TIMP4（金属蛋白酶组织抑制剂 4）并抑制脱氧皮质酮乙酸盐盐诱导的 MMP（基质金属蛋白酶）激活和弹性蛋白断裂。此外，BMAL1 与启动子结合并抑制 转录。
这些结果揭示了 SMC BMAL1 在 AAA 中具有重要但以前未被探索的作用。此外，这些结果确定 TIMP4 是 BMAL1 的一个新靶点，它可能介导 SMC BMAL1 缺失的 AAA 保护作用。
