Department of Cardiology, Hubei Key Laboratory of Cardiology, Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Int J Mol Med. 2018 Mar;41(3):1573-1583. doi: 10.3892/ijmm.2017.3354. Epub 2017 Dec 29.
Peptidyl‑prolyl cis/trans isomerase, NIMA-interacting 1 (Pin1) is a member of a large superfamily of phosphorylation‑dependent peptidyl‑prolyl cis/trans isomerases, which not only regulates multiple targets at various stages of cellular processes, but is also involved in the pathogenesis of several diseases, including microbial infection, cancer, asthma and Alzheimer's disease. However, the role of Pin1 in cardiac fibrosis remains to be fully elucidated. The present study investigated the potential mechanism of Pin1 in isoprenaline (ISO)‑induced myocardial fibrosis in rats. The rats were randomly divided into three groups. Echocardiography was used to evaluate changes in the size, shape and function of the heart, and histological staining was performed to visualize inflammatory cell infiltration and fibrosis. Reverse transcription‑quantitative polymerase chain reaction analysis, immunohistochemistry and Picrosirius red staining were used to differentiate collagen subtypes. Additionally, cardiac‑specific phosphorylation of mitogen‑activated protein kinase kinase 1/2 (MEK1/2) and extracellular‑signal regulated protein kinase 1/2 (ERK1/2), and the activities of Pin1 and α‑smooth muscle actin (α‑SMA) and other oxidative stress parameters were estimated in the heart. The administration of ISO resulted in an increase in cardiac parameters and elevated the heart‑to‑body weight ratio. Histopathological examination of heart tissues revealed interstitial inflammatory cellular infiltrate and disorganized collagen fiber deposition. In addition, lipid peroxidation products and oxidative stress marker activity in plasma and tissues were significantly increased in the ISO‑treated rats. Western blot analysis showed significantly elevated protein levels of phosphorylated Pin1, MEK1/2, ERK1/2 and α‑SMA in remodeling hearts. Treatment with juglone following intraperitoneal injection of ISO significantly prevented inflammatory cell infiltration, improved cardiac function, and suppressed oxidative stresses and fibrotic alterations. In conclusion, the results of the present study suggested that the activation of Pin1 promoted cardiac extracellular matrix deposition and oxidative stress damage by regulating the phosphorylation of the MEK1/2‑ERK1/2 signaling pathway and the expression of α‑SMA. By contrast, the inhibition of Pin1 alleviated cardiac damage and fibrosis in the experimental models, suggesting that Pin1 contributed to the development of cardiac remodeling in ISO‑administered rats, and that the inactivation of Pin1 may be a novel therapeutic candidate for the treatment of cardiovascular disease and heart failure.
肽基脯氨酰顺/反异构酶，牵张蛋白 1（Pin1）是一个大的磷酸化依赖的肽基脯氨酰顺/反异构酶超家族的成员，它不仅调节细胞过程的各个阶段的多个靶标，而且还涉及几种疾病的发病机制，包括微生物感染、癌症、哮喘和阿尔茨海默病。然而，Pin1 在心肌纤维化中的作用仍有待充分阐明。本研究探讨了 Pin1 在异丙肾上腺素（ISO）诱导的大鼠心肌纤维化中的潜在机制。大鼠随机分为三组。超声心动图用于评估心脏大小、形状和功能的变化，组织学染色用于可视化炎症细胞浸润和纤维化。逆转录定量聚合酶链反应分析、免疫组织化学和苦味酸天狼猩红染色用于区分胶原亚型。此外，心脏特异性丝裂原激活的蛋白激酶激酶 1/2（MEK1/2）和细胞外信号调节蛋白激酶 1/2（ERK1/2）的磷酸化，Pin1 和α-平滑肌肌动蛋白（α-SMA）的活性以及心脏中的其他氧化应激参数进行了评估。ISO 的给药导致心脏参数增加，并升高心脏/体重比。心脏组织的组织学检查显示间质炎症细胞浸润和胶原纤维排列紊乱。此外，ISO 处理大鼠的血浆和组织中的脂质过氧化产物和氧化应激标志物活性显著增加。Western blot 分析显示，重塑心脏中磷酸化 Pin1、MEK1/2、ERK1/2 和α-SMA 的蛋白水平显著升高。ISO 腹腔注射后用 Juglone 处理可显著预防炎症细胞浸润，改善心功能，并抑制氧化应激和纤维化改变。综上所述，本研究结果表明，Pin1 的激活通过调节 MEK1/2-ERK1/2 信号通路的磷酸化和α-SMA 的表达，促进心脏细胞外基质的沉积和氧化应激损伤。相反，Pin1 的抑制减轻了实验模型中心脏损伤和纤维化，提示 Pin1 促进了 ISO 给药大鼠心脏重塑的发展，Pin1 的失活可能成为治疗心血管疾病和心力衰竭的新治疗靶点。
