Xie Jiahe, Cui Kai, Hao Huixin, Zhang Yingxue, Lin Hairuo, Chen Zhenhuan, Huang Xiaobo, Cao Shiping, Liao Wangjun, Bin Jianping, Kitakaze Masafumi, Liao Yulin
State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Cardiovasc Diabetol. 2016 Sep 22;15(1):136. doi: 10.1186/s12933-016-0452-z.
Left ventricular (LV) dysfunction is closely associated with LV hypertrophy or diabetes, as well as insufficient autophagic flux. Acute or chronic hyperglycemia is a prognostic factor for patients with myocardial infarction. However, the effect of acute hyperglycemia on LV dysfunction of the hypertrophic heart and the mechanisms involved are still unclear. This study aimed to confirm our hypothesis that either acute or chronic hyperglycemia suppresses LV diastolic function and autophagic flux.
The transverse aortic constriction (TAC) model and streptozocin-induced type 1 diabetic mellitus mice were used. LV function was evaluated with a Millar catheter. Autophagic levels and autophagic flux in the whole heart and cultured neonatal rat cardiomyocytes in response to hyperglycemia were examined by using western blotting of LC3B-II and P62. We also examined the effect of an autophagic inhibitor on LC3B-II and P62 protein expression and LC3 puncta.
In mice with TAC, we detected diastolic dysfunction as early as 30 min after TAC. This dysfunction was indicated by a greater LV end-diastolic pressure and the exponential time constant of LV relaxation, as well as a smaller maximum descending rate of LV pressure in comparison with sham group. Similar results were also obtained in mice with TAC for 2 weeks, in addition to increased insulin resistance. Acute hyperglycemic stress suppressed diastolic function in mice with myocardial hypertrophy, as evaluated by invasive LV hemodynamic monitoring. Mice with chronic hyperglycemia induced by streptozocin showed myocardial fibrosis and diastolic dysfunction. In high glucose-treated cardiomyocytes and streptozocin-treated mice, peroxisome proliferator-activated receptor-γ coactivator 1α was downregulated, while P62 was upregulated. Autophagic flux was also significantly inhibited in response to high glucose exposure in angiotensin-II treated cardiomyocytes.
Acute hyperglycemia suppresses diastolic function, damages mitochondrial energy signaling, and inhibits autophagic flux in prohypertrophic factor-stimulated cardiomyocytes.
左心室（LV）功能障碍与左心室肥厚、糖尿病以及自噬通量不足密切相关。急性或慢性高血糖是心肌梗死患者的一个预后因素。然而，急性高血糖对肥厚性心脏左心室功能障碍的影响及其相关机制仍不清楚。本研究旨在证实我们的假设，即急性或慢性高血糖会抑制左心室舒张功能和自噬通量。
采用横向主动脉缩窄（TAC）模型和链脲佐菌素诱导的1型糖尿病小鼠。用Millar导管评估左心室功能。通过对LC3B-II和P62进行蛋白质免疫印迹法，检测高血糖状态下全心和培养的新生大鼠心肌细胞中的自噬水平和自噬通量。我们还研究了自噬抑制剂对LC3B-II和P62蛋白表达以及LC3斑点的影响。
在TAC小鼠中，我们在TAC后30分钟就检测到舒张功能障碍。与假手术组相比，这种功能障碍表现为左心室舒张末期压力和左心室舒张指数时间常数增加，以及左心室压力最大下降速率减小。在TAC 2周的小鼠中也获得了类似结果，此外还出现了胰岛素抵抗增加。通过有创左心室血流动力学监测评估，急性高血糖应激抑制了心肌肥厚小鼠的舒张功能。链脲佐菌素诱导的慢性高血糖小鼠表现出心肌纤维化和舒张功能障碍。在高糖处理的心肌细胞和链脲佐菌素处理的小鼠中，过氧化物酶体增殖物激活受体γ共激活因子1α下调，而P62上调。在血管紧张素-II处理的心肌细胞中，高糖暴露也显著抑制了自噬通量。
急性高血糖抑制舒张功能，损害线粒体能量信号，并抑制促肥厚因子刺激的心肌细胞中的自噬通量。
