Cardiomyocyte-specific deletion of GSK-3β leads to cardiac dysfunction in a diet induced obesity model.
Cardiomyocyte-specific deletion of GSK-3β leads to cardiac dysfunction in a diet induced obesity model.
复制标题
在饮食诱导的肥胖模型中，心肌细胞特异性删除 GSK-3β 会导致心脏功能障碍。
DOI：
10.1016/j.ijcard.2018.01.013
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发表时间：
2018-05-15
影响因子：
3.5
通讯作者：
Lal H
中科院分区：
文献类型：
--
作者：
Gupte M;Tumuluru S;Sui JY;Singh AP;Umbarkar P;Parikh SS;Ahmad F;Zhang Q;Force T;Lal H
肥胖是心肌疾病发展的独立危险因素，是全球日益严重的医疗保健问题。众所周知，GSK-3β 对于心脏病理生理学至关重要。然而，心肌细胞 (CM) GSK-3β 在饮食引起的心功能障碍中的作用尚不清楚。 CM 特异性 GSK-3β 敲除 (CM-GSK-3β-KO) 和同窝对照 (WT) 小鼠采用对照饮食 (CD) 或高脂饮食 (HFD) 喂养 55 周。通过经胸超声心动图评估心脏功能。在基线时，WT 和 CM-GSK-3β-KO 的体重和心功能相当。然而，高脂饮食喂养的 CM-GSK-3β-KO 小鼠出现了严重的心功能障碍。一致的是，HFD 喂养的 CM-GSK-3β-KO 小鼠的心脏重量/胫骨长度和肺重量/胫骨长度均显着升高。 CM-GSK-3β-KO 中的心脏功能受损和不良心室重塑与体重或瘦/脂肪成分无关，因为 HFD 喂养的 CM-GSK-3β-KO 和对照组表现出相当的体重和体重。在分子水平上，在 CD 上，CM-GSK-3α 补偿了 CM-GSK-3β 的损失，明显减少了 GSK-3αs21 磷酸化（激活），从而保留了经典的 β-连环蛋白泛素化途径和心脏功能。然而，这种保护性代偿机制随着 HFD 的丧失而消失，导致 HFD 喂养的 CM-GSK-3β-KO 心脏中 β-catenin 过度积累，从而导致不良的心室重塑和心功能障碍。总之，这些结果表明心脏 GSK-3β 对于预防肥胖引起的不良心室重塑和心功能障碍至关重要。
Obesity, an independent risk factor for the development of myocardial diseases is a growing healthcare problem worldwide. It’s well established that GSK-3β is critical to cardiac pathophysiology. However, the role cardiomyocyte (CM) GSK-3β in diet-induced cardiac dysfunction is unknown. CM-specific GSK-3β knockout (CM-GSK-3β-KO) and littermate controls (WT) mice were fed either a control diet (CD) or high-fat diet (HFD) for 55 weeks. Cardiac function was assessed by transthoracic echocardiography. At baseline, body weights and cardiac function were comparable between the WT and CM-GSK-3β-KOs. However, HFD-fed CM-GSK-3β-KO mice developed severe cardiac dysfunction. Consistently, both heart weight/tibia length and lung weight/tibia length were significantly elevated in the HFD-fed CM-GSK-3β-KO mice. The impaired cardiac function and adverse ventricular remodeling in the CM-GSK-3β-KOs were independent of body weight or the lean/fat mass composition as HFD-fed CM-GSK-3β-KO and controls demonstrated comparable body weight and body masses. At the molecular level, on a CD, CM-GSK-3α compensated for the loss of CM-GSK-3β, as evident by significantly reduced GSK-3αs21 phosphorylation (activation) resulting in a preserved canonical β-catenin ubiquitination pathway and cardiac function. However, this protective compensatory mechanism is lost with HFD, leading to excessive accumulation of β-catenin in HFD-fed CM-GSK-3β-KO hearts, resulting in adverse ventricular remodeling and cardiac dysfunction. In summary, these results suggest that cardiac GSK-3β is crucial to protect against obesity-induced adverse ventricular remodeling and cardiac dysfunction.
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