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.

心肌梗塞（MI）是全世界死亡的主要原因。糖原合成酶激酶-3（GSK-3）被认为是心血管疾病有前途的治疗靶点。 GSK-3 是普遍表达的丝氨酸/苏氨酸激酶家族。 GSK-3 同工型似乎在心脏中发挥着重叠、独特甚至相反的功能。此前，我们的团队发现心脏成纤维细胞 (FB) GSK-3β 作为缺血心脏纤维化重塑的负调节因子。然而，FB-GSK-3α 在 MI 病理学中的作用尚未明确。为了确定 FB-GSK-3α 在 MI 诱导的不良心脏重塑中的作用，使用他莫昔芬 (TAM) 诱导型 Tcf21 或 Periostin (Postn) 启动子驱动的 Cre 重组酶在驻留成纤维细胞或肌成纤维细胞 (MyoFB) 中特异性删除 GSK-3α ， 分别。超声心动图分析显示，FB 或 MyoFB 特异性 GSK-3α 缺失可防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 组毛细血管密度有所改善，肥大和纤维化显着减少。我们在 MI 后 4 周收获心脏并分析不良重塑的特征基因。具体来说，进行 qPCR 分析以检查炎症（TNFα、IL-6、IL-1β）、纤维化（COL1A1、COL3A1、COMP、Fibronectin-1、潜在 TGF-β 结合蛋白 2）和肥大（ANP）的基因组。 ，BNP，MYH7）。由于 FB 特异性 GSK-3α 缺失，这些分子标记基本上已标准化。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发挥着关键作用，因此，它可以成为治疗靶点。