Abstract：
Cardiac fibrosis is characterized by abnormal proliferation of cardiac fibroblasts (CFs) and ventricular remodeling, which finally leads to heart failure. Inflammation and oxidative stress play a central role in the development of cardiac fibrosis. CyPA (Cyclophilin A) is a main proinflammatory cytokine secreted under the conditions of oxidative stress. The mechanisms by which intracellular and extracellular CyPA interact with CFs are unclear. Male C57BL/6 J mice received angiotensin Ⅱ (Ang Ⅱ) or vehicle for 4 weeks. Inhibition of CyPA significantly reversed Ang Ⅱ-induced cardiac hypertrophy and fibrosis. Mechanically, TGF-β (Transforming growth factor-β) signaling was found to be an indispensable downstream factor of CyPA-mediated myofibroblast differentiation and proliferation. Furthermore, intracellular CyPA and extracellular CyPA activate TGF-β signaling through NOD-like receptor protein 3 (NLRP3) inflammasome and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, respectively. Pharmacological inhibition of CyPA and its receptor CD147 implemented by Triptolide also attenuated the expression of TGF-β signaling and cardiac fibrosis in Ang Ⅱ-model. These studies elucidate a novel mechanism by which CyPA promotes TGF-β and its downstream signaling in CFs and identify CyPA (both intracellular and extracellular) as plausible therapeutic targets for preventing or treating cardiac fibrosis induced by chronic Ang Ⅱ stimulation.
摘要：
心脏纤维化的特征是心脏成纤维细胞（CFs）的异常增殖和心室重构，最终导致心脏衰竭.炎症和氧化应激在心脏纤维化的发展中起着重要作用。CyPA(CyclophilinA)是氧化应激条件下分泌的主要促炎细胞因子。细胞内和细胞外CyPA与CFs相互作用的机制尚不清楚。雄性C57BL/6J小鼠接受血管紧张素Ⅱ（AngⅡ）或载体治疗4周。抑制CyPA可显著逆转AngⅡ诱导的心肌肥厚和纤维化。机械上,发现TGF-β（转化生长因子-β）信号是CyPA介导的肌成纤维细胞分化和增殖的必不可少的下游因子。此外，细胞内CyPA和细胞外CyPA通过NOD样受体蛋白3（NLRP3）炎性体和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶激活TGF-β信号，分别。雷公藤甲素对CyPA及其受体CD147的药理抑制作用也减弱了AngⅡ模型中TGF-β信号和心肌纤维化的表达。这些研究阐明了CyPA在CFs中促进TGF-β及其下游信号传导的新机制，并确定CyPA（细胞内和细胞外）是预防或治疗慢性AngⅡ刺激引起的心脏纤维化的合理治疗靶标。
