Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212000, China.
Department of Geriatrics, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu 212000, China.
Biochem Pharmacol. 2024 Jul;225:116271. doi: 10.1016/j.bcp.2024.116271. Epub 2024 May 7.
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.
心肌纤维化的特征是心肌成纤维细胞（CFs）的异常增殖和心室重构，最终导致心力衰竭。炎症和氧化应激在心肌纤维化的发展中起核心作用。CyPA（亲环素 A）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/6 J 小鼠接受血管紧张素Ⅱ（Ang Ⅱ）或载体 4 周。CyPA 抑制显著逆转了 Ang Ⅱ诱导的心肌肥大和纤维化。在机制上，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不可或缺的下游因子。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）氧化酶分别激活 TGF-β 信号。雷公藤内酯醇通过抑制 CyPA 及其受体 CD147 实现的药理学抑制作用也减弱了 Ang Ⅱ 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及其下游信号的新机制，并将 CyPA（细胞内和细胞外）鉴定为预防或治疗慢性 Ang Ⅱ刺激引起的心肌纤维化的合理治疗靶点。
