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Role of Asymmetric Methylarginine and Connexin 43 in the Regulation of Pulmonary Endothelial Function:

机译:不对称甲基精氨酸和连接蛋白43在调节肺血管内皮功能中的作用:

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Circulating levels of asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, are increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication, required for the coordinated regulation of endothelial barrier function and angiogenesis, and so contributes to pulmonary endothelial dysfunction. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells; pulmonary endothelial microvascular cells from mice deficient in an enzyme metabolizing ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI); and blood-derived endothelial-like cells from patients with IPAH. Exogenous and endogenous ADMA inhibited protein expression and membrane localization of connexin 43 (Cx43) in a nitric oxide/soluble guanosine monophosphate/c-jun-dependent manner in pulmonary endothelial cells, resulting in the inhibition of gap junctional communication, increased permeability, and decreased angiogenesis. The effects of ADMA were prevented by overexpression of DDAHI or Cx43 and by treatment with rotigaptide. Blood-derived endothelial-like cells from IPAH patients displayed a distinct disease-related phenotype compared to cells from healthy controls, characterized by reduced DDAHI expression, increased ADMA production, and abnormal angiogenesis. In summary, we show that ADMA induces pulmonary endothelial dysfunction via changes in expression and activity of Cx43. Cells from IPAH patients exhibit abnormal DDAHI/Cx43 signaling as well as differences in gap junctional communication, barrier function, and angiogenesis. Strategies that promote DDAHI/Cx43 signaling may have an endothelium-protective effect and be beneficial in pulmonary vascular disease.
机译:特发性肺动脉高压(IPAH)患者的一氧化氮合酶抑制剂非对称二甲基精氨酸(ADMA)的循环水平增加。我们假设ADMA消除了间隙屏障连接通讯,这是内皮屏障功能和血管生成的协调调节所必需的,因此导致了肺内皮功能障碍。在人肺动脉内皮细胞中研究了ADMA对间隙连接蛋白表达和功能的影响。来自缺乏代谢ADMA的酶的小鼠肺内皮微血管细胞,二甲基精氨酸二甲基氨基水解酶I(DDAHI);和IPAH患者的血液来源的内皮样细胞。外源性和内源性ADMA以一氧化氮/可溶性鸟苷单磷酸/ c-jun依赖性方式抑制肺血管内皮细胞中连接蛋白43(Cx43)的蛋白表达和膜定位,从而抑制了间隙连接通讯,通透性增加和降低血管生成。通过DDAHI或Cx43的过表达和罗替加肽的治疗可防止ADMA的作用。与来自健康对照的细胞相比,来自IPAH患者的血液来源的内皮样细胞表现出与疾病相关的独特表型,其特征在于DDAHI表达降低,ADMA产生增加以及血管生成异常。总之,我们表明ADMA通过改变Cx43的表达和活性来诱导肺内皮功能障碍。来自IPAH患者的细胞显示出异常的DDAHI / Cx43信号以及间隙连接通讯,屏障功能和血管生成方面的差异。促进DDAHI / Cx43信号传导的策略可能具有内皮保护作用,并且对肺血管疾病有益。

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