PKC-ε-dependent survival signals in diabetic hearts
PKC-ε-dependent survival signals in diabetic hearts
复制标题
DOI：
10.1152/ajpheart.01200.2004
复制
发表时间：
2005-10-01
影响因子：
4.8
通讯作者：
Meggs, LG
中科院分区：
文献类型：
--
作者：
Malhotra, A;Begley, R;Meggs, LG
糖尿病因原发性心肌病的发展而变得复杂，这导致了这种疾病的发病率和死亡率过高。蛋白激酶C（PKC）同工酶家族在出生后发育和病理刺激反应中表达的心脏表型中起着关键作用。高血压是心脏PKC同工酶的激活信号，其调节无数细胞事件，包括细胞死亡和存活。PKC家族的ε-同工酶在心肌细胞中传递强有力的存活信号。因此，为了检验心脏PKC-RACK的内源性激活将保护免于高血糖细胞损伤和左心室功能障碍的假设，在具有PKC-RACK易位激活剂[活化C激酶的psi ε-受体（psi ε-RACK）]的心脏特异性表达的基因工程小鼠中使用链脲佐菌素诱导糖尿病。结果表明，糖尿病psi ε-RACK（ε-激动剂）小鼠中具有显著的PKC-β-心肌保护表型，其特征在于抑制高血糖细胞凋亡信号，减弱高血糖介导的氧化应激，并保留左心室泵功能参数。糖尿病ε-激动剂小鼠的心脏表现出选择性运输PKC β到膜和线粒体隔室，线粒体Bad蛋白的磷酸化/失活，以及细胞色素c释放的抑制。我们的结论是，激活内源性PKC-β在糖尿病ε激动剂小鼠的心脏促进生存表型，减弱氧化应激的标志物，并抑制慢性高血糖症的负性肌力特性。
Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The epsilon-isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC-epsilon will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC-epsilon translocation activator [psi epsilon-receptors for activated C kinase (psi epsilon-RACK)]. The results demonstrate a striking PKC-epsilon cardioprotective phenotype in diabetic psi epsilon-RACK (epsilon-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic epsilon-agonist mice exhibited selective trafficking of PKC-epsilon to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC-epsilon in hearts of diabetic epsilon-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.