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首页> 外文期刊>Circulation research: a journal of the American Heart Association >The GSK-3 Family as Therapeutic Target for Myocardial Diseases
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The GSK-3 Family as Therapeutic Target for Myocardial Diseases

机译：GSK-3家族作为心肌疾病的治疗靶标

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Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer disease, aging, inflammation, and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review, we will focus on its expanding role in the heart, concentrating primarily on recent studies that have used cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis, and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3 alpha specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction after myocardial infarction by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3 beta as a regulator of myocardial fibrosis will also be discussed. We will review our recent findings that specific deletion of GSK-3 beta in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3 beta is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature.
机译：糖原合酶激酶3（GSK-3）是调节真正惊人数量的关键细胞内信号通路的少数信号分子之一。它与多种疾病有关，包括心力衰竭，躁郁症，糖尿病，阿尔茨海默氏病，衰老，炎症和癌症。此外，最近的一项临床试验证实了以小分子抑制剂靶向GSK-3的人类疾病的可行性。在当前的审查中，我们将专注于其在心脏中的扩展作用，主要集中于最近在小鼠模型中使用心肌细胞和成纤维细胞特异性条件基因缺失的研究。我们将重点介绍GSK-3同工型在各种病理状况中的作用，包括心肌衰老，缺血性损伤，心肌纤维化和心肌细胞增殖。我们将讨论我们最近的发现，即心肌细胞中GSK-3 alpha的缺失通过限制疤痕扩展并促进心肌细胞增殖，减轻心肌梗塞后的心室重构和心脏功能障碍。还将讨论GSK-3 beta作为心肌纤维化调节剂的最新出现。我们将回顾我们最近的发现，即心脏成纤维细胞中GSK-3β的特异性缺失会导致纤维生成，左心室功能障碍和缺血性心脏过度瘢痕形成。最后，我们将研究在心脏成纤维细胞中特异删除GSK-3 beta的模型中驱动异常心肌纤维化的潜在机制。我们将总结这些最新结果，并在可能的情况下提供解释，在不可行的情况下提供假设。对于这些研究，我们将严重依赖我们的模型和其他模型，以调和文献中某些明显的不一致之处。

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