Roe Nathan D, Xu Xihui, Kandadi Machender R, Hu Nan, Pang Jiaojiao, Weiser-Evans Mary C M, Ren Jun
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China.
Biochim Biophys Acta. 2015 Feb;1852(2):290-8. doi: 10.1016/j.bbadis.2014.09.002. Epub 2014 Sep 16.
Phosphatase and tensin homolog (PTEN) deleted from chromosome 10 has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca(2+) handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200mg/kg/d, in drinking H2O for 4weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）与心脏内环境稳态的维持有关，但其潜在机制仍不清楚。我们构建了心肌细胞特异性敲除PTEN的小鼠模型，以评估心脏几何形状和收缩功能，以及二甲双胍对PTEN缺乏诱导的心脏异常（如有）的影响。对心脏组织学、自噬及相关信号分子进行了评估。心肌细胞特异性PTEN缺失引发心脏肥大和收缩异常（超声心动图和心肌细胞收缩功能障碍），伴有细胞内Ca(2+)处理受损。PTEN缺失诱导的心脏肥大和收缩异常与PTEN诱导激酶1（Pink1）和AMPK的磷酸化减弱有关。有趣的是，给予AMPK激活剂二甲双胍（200mg/kg/d，溶于饮用水中，持续4周）可挽救PTEN缺失诱导的心脏几何形状和功能缺陷，以及心脏中自噬和自噬流的中断。此外，二甲双胍给药虽部分但显著减轻了PTEN缺失诱导的超氧化物积累。在H9C2成肌细胞中针对Pink1的RNA干扰明显增加了细胞内ATP水平并抑制了AMPK磷酸化，证实了AMPK作为PTEN-Pink1下游靶点的作用。进一步研究发现，分别使用二甲双胍和雷帕霉素激活AMPK和自噬，可挽救PTEN缺失诱导的机械异常，且几乎没有叠加效应。这些数据表明，心肌细胞特异性PTEN缺失导致Pink1-AMPK信号缺失、心脏肥大和收缩缺陷的发生。AMPK的激活挽救了PTEN缺失诱导的与自噬和自噬流恢复相关的心脏异常。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。
