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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Overexpression of Gsalpha compensates for myocyte loss in diabetic cardiomyopathy.
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Overexpression of Gsalpha compensates for myocyte loss in diabetic cardiomyopathy.

机译:Gsalpha的过表达补偿了糖尿病性心肌病中的心肌细胞丢失。

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The stimulatory G protein Gsalpha transmits signals from activated beta-adrenergic receptors via the cyclic AMP-PKA pathway, targeting the key regulatory protein phospholamban. We hypothesized that mice with intrinsic activation of cardiac Gsalpha are resistant to the development of the diabetic cardiomyopathy phenotype. Accordingly, streptozotocin (STZ)-diabetes mellitus was induced in genetically engineered mice with cardiac-specific Gsalpha overexpression and in nontransgenic (NTG) littermates. At 8 weeks, Gsalpha diabetic mice showed no impairment of LV contractility nor increase in myocyte apoptosis, whereas NTG diabetic mice showed a 30% decrease in +dP/dt and -dP/dt with sustained (3-fold) myocyte loss by apoptosis. To assess the level of myocardial reactive oxygen species, we measured malondialdehyde, a surrogate marker of oxidative stress, which was increased in the hearts of NTG and Gsalpha diabetic mice. In addition, chronic hyperglycemia also increased the activity of catalase and superoxide dismutase in the hearts of NTG and Gsalpha diabetic mice. Hearts of NTG diabetic mice, but not Gsalpha mice, showed increased expression of proapoptosis Bax, downregulation in Bcl2, and an increase in the Bax/Bcl2 ratio. Hearts of NTG diabetic mice showed 60% reduction in phosphorylation at the critical Ser16 residue of phospholamban, whereas phosphorylation at Ser16 was restored in hearts of Gsalpha-diabetic mice. We conclude that cardiac-specific overexpression of Gsalpha compensates for the loss of cardiac function in diabetes mellitus.
机译:刺激性G蛋白Gsalpha通过循环的AMP-PKA途径从激活的β-肾上腺素受体传输信号,靶向关键的调节蛋白phosphorlamban。我们假设具有心脏Gsalpha内在激活的小鼠对糖尿病性心肌病表型的发展有抵抗力。因此,在具有心脏特异性Gsalpha过表达的基因工程小鼠和非转基因(NTG)同窝出生的小鼠中诱导了链脲佐菌素(STZ)-糖尿病。在8周时,Gsalpha糖尿病小鼠未表现出LV收缩力受损,也没有心肌细胞凋亡增加,而NTG糖尿病小鼠表现出+ dP / dt和-dP / dt降低30%,并伴随细胞凋亡持续(3倍)丢失。为了评估心肌活性氧的水平,我们测量了丙二醛,这是氧化应激的替代标志物,其在NTG和Gsalpha糖尿病小鼠的心脏中增加。此外,慢性高血糖症还增加了NTG和Gsalpha糖尿病小鼠心脏中过氧化氢酶和超氧化物歧化酶的活性。 NTG糖尿病小鼠的心脏(而非Gsalpha小鼠)的心脏显示出凋亡的Bax表达增加,Bcl2的下调以及Bax / Bcl2比的增加。 NTG糖尿病小鼠的心脏显示磷酸lamban的关键Ser16残基的磷酸化减少了60%,而Ser16的磷酸化在Gsalpha糖尿病小鼠的心脏中得以恢复。我们得出的结论是,Gsalpha的心脏特异性过度表达可以补偿糖尿病患者心脏功能的丧失。

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