Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China.
State Key Laboratory of Diabetes and Obesity Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China.
Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1258-H1268. doi: 10.1152/ajpheart.00274.2018. Epub 2018 Aug 24.
Bariatric surgery has been reported to relieve diabetic cardiomyopathy (DCM) effectively. However, the mechanisms remain largely unknown. To determine the effects of bariatric surgery on DCM via modulation of myocardial Ca homeostasis and autophagy, sleeve gastrectomy (SG), duodenal-jejunal bypass (DJB), and sham surgeries were performed in diabetic rats induced by high-fat diet and a low dose of streptozotocin. Cardiac remodeling was assessed by a series of morphometric and histological analyses. Transthoracic echocardiography and hemodynamic measurements were performed to determine cardiac function. Ca homeostasis was evaluated by measuring Ca transients with fura-2 AM in isolated ventricular myocytes along with detection of the abundance of Ca regulatory proteins in the myocardium. Myocardial autophagic flux was determined by expression of autophagy-related proteins in the absence and presence of chloroquine. Both SG and DJB surgery alleviated DCM morphologically and functionally. Ca transients exhibited a significantly higher amplitude and faster decay after SG and DJB, which could be partially explained by increased expression of ryanodine receptor 2, sarco(endo)plasmic reticulum Ca-2ATPase, 12.6-kDa FK506-binding protein, and hyperphosphorylation of phospholamban. In addition, a lower level of light chain 3B and higher level of p62 were detected after both SG and DJB, which was not reversed by chloroquine treatment and associated with activated mammalian target of rapamycin and attenuated AMP-activated protein kinase signaling pathway. Collectively, these results provided evidence that bariatric surgery could alleviate DCM effectively, which may result, at least in part, from facilitated Ca homeostasis and attenuated autophagy, suggesting a potential choice for treatment of DCM when properly implemented. NEW & NOTEWORTHY The present study is the first to investigate the modulation of myocardial Ca homeostasis and autophagy after bariatric surgery and to examine its effects on diabetic cardiomyopathy. Bariatric surgery could facilitate myocardial Ca homeostasis and attenuate myocardial autophagy, contributing to the alleviation of cardiomyopathy morphologically and functionally in a diabetic rat model.
减重手术已被报道可有效缓解糖尿病性心肌病(DCM)。然而,其机制在很大程度上尚不清楚。为了通过调节心肌钙稳态和自噬来确定减重手术对 DCM 的影响,在高脂肪饮食和低剂量链脲佐菌素诱导的糖尿病大鼠中进行了袖状胃切除术(SG)、十二指肠空肠旁路术(DJB)和假手术。通过一系列形态学和组织学分析评估心脏重构。经胸超声心动图和血流动力学测量用于确定心脏功能。通过在分离的心室肌细胞中用 fura-2 AM 测量 Ca 瞬变以及检测心肌中 Ca 调节蛋白的丰度来评估 Ca 稳态。通过在没有和存在氯喹的情况下表达自噬相关蛋白来确定心肌自噬通量。SG 和 DJB 手术均在形态和功能上缓解了 DCM。SG 和 DJB 后 Ca 瞬变的幅度显著增加,衰减速度加快,这可以部分解释为肌质网 Ca2+-ATP 酶、12.6 kDa FK506 结合蛋白和磷蛋白的表达增加,ryanodine 受体 2 快速降解。此外,在 SG 和 DJB 后均检测到轻链 3B 水平降低和 p62 水平升高,但氯喹处理不能逆转这种情况,并且与激活的哺乳动物雷帕霉素靶蛋白和减弱的 AMP 激活的蛋白激酶信号通路有关。总之,这些结果提供了证据表明减重手术可有效缓解 DCM,这至少部分归因于促进的 Ca 稳态和减弱的自噬,表明在适当实施时,这可能是 DCM 治疗的一种选择。
本研究首次研究了减重手术后心肌 Ca 稳态和自噬的调节,并研究了其对糖尿病性心肌病的影响。减重手术可以促进心肌 Ca 稳态并减轻心肌自噬,从而在糖尿病大鼠模型中在形态和功能上缓解心肌病。