心脏成纤维细胞GSK-3α通过促进纤维化、炎症和损害血管生成加重缺血性心脏损伤。

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2023-09-01 DOI:10.1007/s00395-023-01005-1
Prachi Umbarkar, Suma Ejantkar, Sulivette Y Ruiz Ramirez, Angelica Toro Cora, Qinkun Zhang, Sultan Tousif, Hind Lal
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引用次数: 0

摘要

心肌梗死(MI)是世界范围内导致死亡的主要原因。糖原合成酶激酶-3 (GSK-3)被认为是一种有前景的治疗心血管疾病的靶点。GSK-3是一个普遍表达的丝氨酸/苏氨酸激酶家族。GSK-3亚型似乎在心脏中发挥重叠、独特甚至相反的功能。之前,我们的研究小组发现,心脏成纤维细胞(FB) GSK-3β在缺血心脏中作为纤维化重塑的负调节因子。然而,FB-GSK-3α在心肌梗死病理中的作用尚未明确。为了确定FB-GSK-3α在mi诱导的不良心脏重构中的作用,分别使用他莫昔芬(TAM)诱导的Tcf21或Periostin (Postn)启动子驱动的Cre重组酶,在居住成纤维细胞或肌成纤维细胞(MyoFB)中特异性地删除GSK-3α。超声心动图分析显示FB-或myofb特异性GSK-3α缺失可阻止扩张性重构和心功能障碍的发生。形态计量学和组织学研究证实,KO组毛细血管密度改善,肥厚和纤维化显著减少。我们在心肌梗死后4周采集心脏,分析不良重构的特征基因。具体而言,采用qPCR分析检测炎症(TNFα、IL-6、IL-1β)、纤维化(COL1A1、COL3A1、COMP、Fibronectin-1、Latent TGF-β结合蛋白2)和肥大(ANP、BNP、MYH7)基因组。由于fb特异性GSK-3α缺失,这些分子标记基本上归一化。进一步的分子研究证实FB-GSK-3α可以调节NF-kB的激活和血管生成相关蛋白的表达。我们的研究结果表明FB-GSK-3α在缺血性心脏的病理性心脏重塑中起关键作用,因此可以作为治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis.

Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1β), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-β binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted.

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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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