Department of Cardiology, Second Affiliated Hospital of Air Forced Military Medical University, Xi'an, Shaanxi Province, 710068, China; Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, 710068, China.
Department of Cardiology, Southwest Medical University, Luzhou, Sichuan Province, 646000, China.
Chem Biol Interact. 2019 Apr 1;302:11-21. doi: 10.1016/j.cbi.2019.01.031. Epub 2019 Jan 29.
Angiotensin II-related cardiac fibrosis is one of the key pathological changes of the hypertrophied left ventricle in various heart disease. Irisin was recently reported to confer cardio-protective and anti-oxidative effects, while whether it can reverse the renin-angiotensin-aldosterone system(RAAS) activation related(angiotensin II-induced) cardiac fibrosis is unknown. In this study, we found that angiotensin II-induced cardiac dysfunction and fibrotic responses were dampened by irisin treatment in mice. Mechanistically, angiotensin II induced robust ROS generation, which in turn triggered activation of pro-fibrotic TGFβ1-Smad2/3 signaling and subsequent collagen synthesis and fibroblast-myofibroblast transformation in cardiac fibroblasts. In contrast, Irisin treatment suppressed angiotensin II-induced ROS generation, TGFβ1 activation, collagen synthesis and fibroblast-myofibroblast transformation, the effects of which was accompanied by Nrf2 activation and also abolished by a Nrf2 targeted siRNA. Taken together, we here identified irisin as a promising anti-fibrotic therapeutic for angiotensin II-related cardiac fibrosis.
血管紧张素 II 相关的心肌纤维化是各种心脏疾病中左心室肥厚的关键病理变化之一。鸢尾素最近被报道具有心脏保护和抗氧化作用，然而，它是否能逆转肾素-血管紧张素-醛固酮系统（RAAS）激活相关（血管紧张素 II 诱导）的心肌纤维化尚不清楚。在本研究中，我们发现鸢尾素处理可减轻血管紧张素 II 诱导的小鼠心脏功能障碍和纤维化反应。在机制上，血管紧张素 II 诱导产生大量的 ROS，进而触发心肌成纤维细胞中促纤维化 TGFβ1-Smad2/3 信号的激活，随后导致胶原合成和纤维母细胞-肌成纤维细胞转化。相比之下，鸢尾素处理抑制了血管紧张素 II 诱导的 ROS 生成、TGFβ1 激活、胶原合成和纤维母细胞-肌成纤维细胞转化，这些作用伴随着 Nrf2 的激活，而 Nrf2 靶向的 siRNA 则消除了这些作用。综上所述，我们确定鸢尾素是一种有前途的抗纤维化治疗药物，可用于治疗血管紧张素 II 相关的心肌纤维化。
