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首页> 外文期刊>Cellular Signalling >Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4
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Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4

机译：G蛋白偶联受体激酶2调节细胞氧化应激和凋亡NADPH氧化酶4的作用

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Cardiac myocyte oxidative stress and apoptosis are considered important mechanisms for the development of heart failure (HF). Chronic HF is characterized by increased circulating catecholamines to augment cardiac output. Long-term stimulation of myocardial p-adrenergic receptors (beta-ARs) is deleterious in cardiac myocytes, however, the potential mechanisms underlying increased cell death are unclear. We hypothesize that GRK2, a critical regulator of myocardial beta-AR signaling, plays an important role in mediating cellular oxidative stress and apoptotic cell death in response to beta-agonist stimulation. Stimulation of H9c2 cells with a non-selective beta-agonist, isoproterenol (Iso) caused increased oxidative stress and apoptosis. There was also increased Nox4 expression, but no change in Nox2, the primary NADPH isoforms and major sources of ROS generation in cardiac myocytes. Adenoviral-mediated overexpression of GRK2 led to similar increases in ROS production and apoptosis as seen with Iso stimulation. These increases in oxidative stress were abolished by pre-treatment with the nonspecific Nox inhibitor, apocynin, or siRNA knockdown of Nox4. Adenoviral-mediated expression of a GRK2 inhibitor prevented ROS production and apoptosis in response to Iso stimulation. beta-Arrestins are signaling proteins that function downstream of GRK2 in beta-AR uncoupling. Adenoviral-mediated overexpression of beta-arrestins increased ROS production and Nox4 expression. Chronic beta-agonist stimulation in mice increased Nox4 expression and apoptosis compared to PBS or AngII treatment. These data demonstrate that GRK2 may play an important role in regulating oxidative stress and apoptosis in cardiac myocytes and provides an additional novel mechanism for the beneficial effects of cardiac-targeted GRK2 inhibition to prevent the development of HF. (C) 2015 Elsevier Inc. All rights reserved.
机译：心脏心肌细胞的氧化应激和凋亡被认为是发展心力衰竭（HF）的重要机制。慢性HF的特征是循环儿茶酚胺增加，以增加心输出量。长期刺激心肌的p-肾上腺素能受体（β-ARs）在心肌细胞中是有害的，但是，导致细胞死亡增加的潜在机制尚不清楚。我们假设，GRK2，心肌β-AR信号的关键调节器，在介导细胞氧化应激和响应β-激动剂刺激的凋亡性细胞死亡中起重要作用。用非选择性β激动剂异丙肾上腺素（Iso）刺激H9c2细胞会导致氧化应激和细胞凋亡增加。 Nox4表达也增加，但Nox2，主要的NADPH亚型和心肌细胞中ROS产生的主要来源没有变化。腺病毒介导的GRK2过表达导致了Iso刺激下ROS产生和凋亡的类似增加。通过用非特异性Nox抑制剂，Apocynin或Nox4的siRNA敲除进行预处理，可以消除这些氧化应激的增加。腺病毒介导的GRK2抑制剂的表达阻止了ROS的产生和细胞对Iso刺激的反应。 β-Arrestins是在β-AR解偶联中在GRK2下游起作用的信号蛋白。腺病毒介导的β-arrestins的过表达增加了ROS的产生和Nox4的表达。与PBS或AngII处理相比，小鼠的慢性β-激动剂刺激增加Nox4表达和细胞凋亡。这些数据表明，GRK2可能在调节心肌细胞的氧化应激和细胞凋亡中起重要作用，并为抑制以心脏为靶点的GRK2阻止HF的发展提供了新的机制。 （C）2015 Elsevier Inc.保留所有权利。

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