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首页> 外文期刊>Journal of Cellular Physiology >Attenuated vasodilatation in lambs with endogenous and exogenous activation of cGMP signaling: role of protein kinase G nitration.
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Attenuated vasodilatation in lambs with endogenous and exogenous activation of cGMP signaling: role of protein kinase G nitration.

机译：减毒血管舒张与内生羊羔和外生cGMP的激活信号:角色蛋白激酶G硝化。

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摘要

Pulmonary vasodilation is mediated through the activation of protein kinase G (PKG) via a signaling pathway involving nitric oxide (NO), natriuretic peptides (NP), and cyclic guanosine monophosphate (cGMP). In pulmonary hypertension secondary to congenital heart disease, this pathway is endogenously activated by an early vascular upregulation of NO and increased myocardial B-type NP expression and release. In the treatment of pulmonary hypertension, this pathway is exogenously activated using inhaled NO or other pharmacological agents. Despite this activation of cGMP, vascular dysfunction is present, suggesting that NO-cGMP independent mechanisms are involved and were the focus of this study. Exposure of pulmonary artery endothelial or smooth muscle cells to the NO donor, Spermine NONOate (SpNONOate), increased peroxynitrite (ONOO(-) ) generation and PKG-1alpha nitration, while PKG-1alpha activity was decreased. These changes were prevented by superoxide dismutase (SOD) or manganese(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) and mimicked by the ONOO(-) donor, 3-morpholinosydnonimine N-ethylcarbamide (SIN-1). Peripheral lung extracts from 4-week old lambs with increased pulmonary blood flow and pulmonary hypertension (Shunt lambs with endogenous activation of cGMP) or juvenile lambs treated with inhaled NO for 24 h (with exogenous activation of cGMP) revealed increased ONOO(-) levels, elevated PKG-1alpha nitration, and decreased kinase activity without changes in PKG-1alpha protein levels. However, in Shunt lambs treated with L-arginine or lambs administered polyethylene glycol conjugated-SOD (PEG-SOD) during inhaled NO exposure, ONOO(-) and PKG-1alpha nitration were diminished and kinase activity was preserved. Together our data reveal that vascular dysfunction can occur, despite elevated levels of cGMP, due to PKG-1alpha nitration and subsequent attenuation of activity.
机译：肺血管扩张是通过介导的激活蛋白激酶G (PKG)通过信号通路包括一氧化氮(NO)、利钠肽(NP)和环鸟苷一磷酸(cGMP)。次要的先天性心脏病,这通路是内生由早期的激活血管upregulation和增加心肌b型NP表达和释放。肺动脉高压的治疗,这一点途径是使用吸入体内激活或其他药物。激活cGMP,血管功能障碍现在,这表明NO-cGMP独立机制的重点本研究。内皮细胞和平滑肌细胞捐赠者,精胺NONOate (SpNONOate)增加生成和过氧亚硝基(ONOO (-))PKG-1alpha硝化,PKG-1alpha活动是降低了。超氧化物歧化酶(SOD)

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