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通过 CREB 的骨膜蛋白上调参与心肌梗死后心肌纤维化。

Upregulation of Periostin Through CREB Participates in Myocardial Infarction-induced Myocardial Fibrosis.

机构信息

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.

Beijing Key Laboratory for Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China; and.

出版信息

J Cardiovasc Pharmacol. 2022 May 1;79(5):687-697. doi: 10.1097/FJC.0000000000001244.

Abstract

Myocardial fibrosis after myocardial infarction (MI) leads to heart failure, which has become an important global public health issue. One of the most important features of myocardial fibrosis is the abnormal deposition of extracellular matrix (ECM) proteins. Periostin is one of the ECM proteins. Cyclic AMP response element-binding protein 1 (CREB) is well known for its involvement in multiple signaling in myocardial fibrosis. It has been confirmed that CREB could regulate ECM proteins deposition. However, little is known about the relationship between CREB and periostin post-MI. This study aims to verify the hypothesis that CREB promotes the expression of periostin in MI-induced myocardial fibrosis. To test this hypothesis, primary rat cardiac fibroblasts were cultured and rat model of MI was established. The level of myocardial fibrosis post-MI was identified by histological staining. The expressions of CREB and periostin were detected through western blot and reverse transcription quantity polymerase chain reaction. The upregulation and downregulation of CREB and periostin were established by plasmid, small interfere RNA (siRNA), and lentivirus, respectively. High levels of CREB and periostin were found post-MI in our study. Meanwhile, the expression of periostin was decreased after CREB downregulation both in vivo and in vitro. Finally, with the treatment of pAV-CREB and si-periostin, the expressions of collagen Ⅰ and Ⅲ were attenuated. The expression of periostin was elevated post-MI and participated in MI-induced myocardial fibrosis, which was regulated through CREB. This study provides a novel idea and potential intervention target for MI-induced myocardial fibrosis.

摘要

心肌梗死后心肌纤维化导致心力衰竭,这已成为一个重要的全球公共卫生问题。心肌纤维化的一个最重要特征是细胞外基质 (ECM) 蛋白的异常沉积。骨桥蛋白是 ECM 蛋白之一。环磷酸腺苷反应元件结合蛋白 1 (CREB) 以其参与心肌纤维化的多种信号转导而闻名。已经证实 CREB 可以调节 ECM 蛋白的沉积。然而,关于 CREB 与心肌梗死后骨桥蛋白之间的关系知之甚少。本研究旨在验证 CREB 促进 MI 诱导的心肌纤维化中骨桥蛋白表达的假说。为了验证这一假说,培养原代大鼠心肌成纤维细胞并建立大鼠 MI 模型。通过组织学染色鉴定 MI 后心肌纤维化的程度。通过 Western blot 和逆转录定量聚合酶链反应检测 CREB 和骨桥蛋白的表达。通过质粒、小干扰 RNA (siRNA) 和慢病毒分别上调和下调 CREB 和骨桥蛋白。在我们的研究中发现 MI 后 CREB 和骨桥蛋白水平升高。同时,体内和体外 CREB 下调后骨桥蛋白的表达减少。最后,用 pAV-CREB 和 si-periostin 处理后,胶原 Ⅰ和 Ⅲ的表达减弱。MI 后骨桥蛋白表达升高,并通过 CREB 参与 MI 诱导的心肌纤维化。该研究为 MI 诱导的心肌纤维化提供了新的思路和潜在的干预靶点。

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