Medical Department of Southeast University, Nanjing, China.
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Eur J Pharmacol. 2020 Sep 15;883:173384. doi: 10.1016/j.ejphar.2020.173384. Epub 2020 Jul 22.
Alamandine attenuates hypertension and cardiac remodeling in spontaneously hypertensive rats (SHRs). We examined whether alamandine attenuates vascular remodeling in mice, and regulates angiotensin II (Ang II)-induced fibrosis in rat vascular smooth muscle cells (VSMCs). Alamandine attenuated hypertension in mice induced by Ang II. Ang II increased the fibrosis of thoracic aorta in mice, which was attenuated by alamandine treatment. Increased levels of collagen I, transforming growth factor-β (TGF-β), and connective tissue growth factor (CTGF) levels in thoracic aortas after Ang II treatment in mice were inhibited by alamandine. Ang II-stimulated collagen I, TGF-β, and CTGF level increases were inhibited by alamandine in rat VSMCs. This could be reversed by Mas-related G protein-coupled receptor, member D (MrgD) antagonist D-Pro-Ang-(1-7) but not Mas receptor antagonist A779. MrgD expression was increased in the thoracic aortas of mice or VSMCs treatment with Ang II. Ang II increased p-p38 and cAMP levels in rat VSMCs, and alamandine blocked Ang II-induced these increases. Cyclic adenosine monophosphate (cAMP) reversed the inhibitory effects of alamandine on the Ang II-induced increases in collagen I, TGF-β, and CTGF levels. These results demonstrate alamandine attenuates vascular fibrosis by stimulating MrgD expression and decreases arterial fibrosis by blocking p-p38 expression. Alamandine/MrgD axis is a potential target for the treatment of vascular remodeling.
阿拉曼丁可减轻自发性高血压大鼠（SHR）的高血压和心脏重构。我们研究了阿拉曼丁是否可减轻小鼠的血管重构，并调节血管平滑肌细胞（VSMC）中的血管紧张素 II（Ang II）诱导的纤维化。阿拉曼丁可减轻 Ang II 诱导的小鼠高血压。Ang II 增加了小鼠胸主动脉的纤维化，而阿拉曼丁治疗可减轻这种纤维化。Ang II 处理后，小鼠胸主动脉中胶原蛋白 I、转化生长因子-β（TGF-β）和结缔组织生长因子（CTGF）水平升高，而阿拉曼丁可抑制其升高。Ang II 刺激的胶原 I、TGF-β和 CTGF 水平升高可被阿拉曼丁在大鼠 VSMC 中抑制，这种抑制可被 MrgD 相关 G 蛋白偶联受体成员 D（MrgD）拮抗剂 D-Pro-Ang-（1-7）逆转，但不能被 Mas 受体拮抗剂 A779 逆转。MrgD 表达在 Ang II 处理的小鼠胸主动脉或 VSMC 中增加。Ang II 增加了大鼠 VSMC 中的 p-p38 和 cAMP 水平，而阿拉曼丁可阻断 Ang II 诱导的这些增加。环磷酸腺苷（cAMP）逆转了阿拉曼丁对 Ang II 诱导的胶原 I、TGF-β和 CTGF 水平升高的抑制作用。这些结果表明，阿拉曼丁通过刺激 MrgD 表达减轻血管纤维化，并通过阻断 p-p38 表达减少动脉纤维化。阿拉曼丁/MrgD 轴可能是治疗血管重构的潜在靶点。
