Kandadi Machender R, Panzhinskiy Evgeniy, Roe Nathan D, Nair Sreejayan, Hu Dahai, Sun Aijun
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
Department of Burn and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, P.R. China.
Biochim Biophys Acta. 2015 Feb;1852(2):299-309. doi: 10.1016/j.bbadis.2014.07.004. Epub 2014 Jul 10.
Obesity-induced cardiomyopathy may be mediated by alterations in multiple signaling cascades involved in glucose and lipid metabolism. Protein tyrosine phosphatase-1B (PTP1B) is an important negative regulator of insulin signaling. This study was designed to evaluate the role of PTP1B in high fat diet-induced cardiac contractile anomalies. Wild-type and PTP1B knockout mice were fed normal (10%) or high (45%) fat diet for 5months prior to evaluation of cardiac function. Myocardial function was assessed using echocardiography and an Ion-Optix MyoCam system. Western blot analysis was employed to evaluate levels of AMPK, mTOR, raptor, Beclin-1, p62 and LC3-II. RT-PCR technique was employed to assess genes involved in hypertrophy and lipid metabolism. Our data revealed increased LV thickness and LV chamber size as well as decreased fractional shortening following high fat diet intake, the effect was nullified by PTP1B knockout. High fat diet intake compromised cardiomyocyte contractile function as evidenced by decreased peak shortening, maximal velocity of shortening/relengthening, intracellular Ca²⁺ release as well as prolonged duration of relengthening and intracellular Ca²⁺ decay, the effects of which were alleviated by PTP1B knockout. High fat diet resulted in enlarged cardiomyocyte area and increased lipid accumulation, which were attenuated by PTP1B knockout. High fat diet intake dampened myocardial autophagy as evidenced by decreased LC3-II conversion and Beclin-1, increased p62 levels as well as decreased phosphorylation of AMPK and raptor, the effects of which were significantly alleviated by PTP1B knockout. Pharmacological inhibition of AMPK using compound C disengaged PTP1B knockout-conferred protection against fatty acid-induced cardiomyocyte contractile anomalies. Taken together, our results suggest that PTP1B knockout offers cardioprotection against high fat diet intake through activation of AMPK. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
肥胖诱导的心肌病可能由参与葡萄糖和脂质代谢的多个信号级联改变介导。蛋白酪氨酸磷酸酶-1B（PTP1B）是胰岛素信号的重要负调节因子。本研究旨在评估PTP1B在高脂饮食诱导的心脏收缩异常中的作用。在评估心脏功能之前，将野生型和PTP1B基因敲除小鼠分别喂食正常（10%）或高脂肪（45%）饮食5个月。使用超声心动图和Ion-Optix MyoCam系统评估心肌功能。采用蛋白质印迹分析评估AMPK、mTOR、猛禽、Beclin-1、p62和LC3-II的水平。采用RT-PCR技术评估参与肥大和脂质代谢的基因。我们的数据显示，高脂饮食摄入后左心室厚度和左心室腔大小增加，缩短分数降低，而PTP1B基因敲除可消除这种影响。高脂饮食摄入损害了心肌细胞的收缩功能，表现为缩短峰值降低、缩短/再延长的最大速度降低、细胞内Ca²⁺释放减少以及再延长持续时间和细胞内Ca²⁺衰减延长，而PTP1B基因敲除可减轻这些影响。高脂饮食导致心肌细胞面积增大和脂质积累增加，而PTP1B基因敲除可使其减弱。高脂饮食摄入抑制了心肌自噬，表现为LC3-II转化和Beclin-1减少、p62水平增加以及AMPK和猛禽磷酸化减少，而PTP1B基因敲除可显著减轻这些影响。使用化合物C对AMPK进行药理抑制可消除PTP1B基因敲除赋予的对脂肪酸诱导的心肌细胞收缩异常的保护作用。综上所述，我们的结果表明，PTP1B基因敲除通过激活AMPK对高脂饮食摄入提供心脏保护。本文是名为：心脏代谢疾病中的自噬和蛋白质质量控制的特刊的一部分。
