PDCD4 缺乏可改善 2 型糖尿病心肌病大鼠模型的左心室重构和胰岛素抵抗。
PDCD4 deficiency ameliorates left ventricular remodeling and insulin resistance in a rat model of type 2 diabetic cardiomyopathy.
机构信息
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
出版信息
BMJ Open Diabetes Res Care. 2020 Apr;8(1). doi: 10.1136/bmjdrc-2019-001081.
OBJECTIVE
Diabetic cardiomyopathy (DCM) is characterized by cardiac remodeling, dysfunction, and insulin resistance; however, the underlying mechanism has not been fully elucidated. Programmed cell death 4 (PDCD4) is a novel inflammation and apoptosis gene, but its role in type 2 DCM remains elusive. We aimed to determine if PDCD4 intervention improves DCM by affecting left ventricular remodeling, function, and insulin resistance.
RESEARCH DESIGN AND METHODS
We designed a PDCD4 rat, established a type 2 diabetes animal model, and constructed a PDCD4 overexpressed adenovirus and PDCD4 small interfer RNA (siRNA) vectors to alter PDCD4 expression in H9c2 cardiomyocytes. Thereafter, glucose levels, lipid metabolism, echocardiography, and extent of myocardial fibrosis, inflammation, and apoptosis were compared in vivo and in vitro.
RESULTS
PDCD4 deficiency improved insulin resistance, cardiac remodeling, and dysfunction in type 2 DCM rats and improved myocardial hypertrophy, fibrosis, inflammation, and apoptosis. Proliferation and transformation of cardiac fibroblasts was reduced via PDCD4 downregulation in vitro under high-glucose stimulation. Furthermore, PDCD4 regulated the myocardial phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathway in vivo and in vitro. PDCD4 intervention affected cardiac remodeling, dysfunction, and insulin resistance by influencing fibrosis, inflammation, and apoptosis via the PI3K-AKT pathway in vivo.
CONCLUSIONS
PDCD4 knockdown protected against left ventricular remodeling, dysfunction, and insulin resistance in type 2 DCM rats. The underlying mechanisms may involve reducing cardiomyocyte apoptosis, inflammation, fibrosis, and normalized PI3K-AKT phosphorylation. To the best of our knowledge, our study is the first to report the effects and underlying mechanisms of PDCD4 in type 2 DCM. These results provide a potential new treatment avenue for improving the prognosis of patients with type 2 DCM.
目的
糖尿病心肌病（DCM）的特征是心脏重构、功能障碍和胰岛素抵抗；然而，其潜在机制尚未完全阐明。程序性细胞死亡因子 4（PDCD4）是一种新的炎症和凋亡基因，但它在 2 型 DCM 中的作用仍不清楚。我们旨在确定 PDCD4 干预是否通过影响左心室重构、功能和胰岛素抵抗来改善 DCM。
研究设计和方法
我们设计了 PDCD4 大鼠，建立了 2 型糖尿病动物模型，并构建了 PDCD4 过表达腺病毒和 PDCD4 小干扰 RNA（siRNA）载体，以改变 H9c2 心肌细胞中的 PDCD4 表达。然后，在体内和体外比较了血糖水平、脂代谢、超声心动图以及心肌纤维化、炎症和细胞凋亡的程度。
结果
PDCD4 缺乏改善了 2 型 DCM 大鼠的胰岛素抵抗、心脏重构和功能障碍，并改善了心肌肥大、纤维化、炎症和细胞凋亡。在高糖刺激下，PDCD4 下调减少了心脏成纤维细胞的增殖和转化。此外，PDCD4 在体内和体外调节心肌磷脂酰肌醇 3-激酶-蛋白激酶 B（PI3K-AKT）通路。PDCD4 干预通过影响纤维化、炎症和细胞凋亡来影响 PI3K-AKT 通路，从而影响体内左心室重构、功能障碍和胰岛素抵抗。
结论
PDCD4 敲低可预防 2 型 DCM 大鼠的左心室重构、功能障碍和胰岛素抵抗。其潜在机制可能涉及减少心肌细胞凋亡、炎症、纤维化和正常化的 PI3K-AKT 磷酸化。据我们所知，我们的研究首次报道了 PDCD4 在 2 型 DCM 中的作用和潜在机制。这些结果为改善 2 型 DCM 患者的预后提供了一个潜在的新治疗途径。
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