Endothelial dysfunction in adiponectin deficiency and its mechanisms involved.
Endothelial dysfunction in adiponectin deficiency and its mechanisms involved.
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脂联素缺乏及其机制中的内皮功能障碍。
DOI：
10.1016/j.yjmcc.2008.10.014
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发表时间：
2009-03
影响因子：
5
通讯作者：
Ma, Xin L.
中科院分区：
文献类型：
--
作者：
Cao, Yu;Tao, Ling;Yuan, Yuexing;Jiao, Xiangying;Lau, Wayne Bond;Wang, Yajing;Christopher, Theodore;Lopez, Bernard;Chan, Lawrence;Goldstein, Barry;Ma, Xin L.
内皮功能障碍是糖尿病血管损伤的早期病理改变，在动脉粥样硬化的发展中起着至关重要的作用。糖尿病患者血浆脂联素（APN）水平显著降低，但其与内皮功能障碍的关系尚不清楚。APN是一种新的血管保护脂肪细胞因子。本研究旨在确定APN缺乏是否可能导致内皮功能障碍，并探讨其相关机制。用野生型（WT）或APN基因敲除（APN-/-）小鼠的主动脉血管制备血管环。检测内皮功能、总NO生成、eNOS表达/磷酸化、超氧化物生成和过氧亚硝酸盐形成。乙酰胆碱和酸化的NaNO2（分别为内皮依赖性和非依赖性血管扩张剂）在WT血管环中引起类似的浓度依赖性血管松弛。APN-/-环对酸化NaNO2的反应正常，但对ACh的反应明显降低（与WT相比降低50%，P<0.01）。APN-/-血管的超氧化物和过氧亚硝酸盐产量均增加（P<0.01）。预处理超氧化物清除剂铁显著，但不完全恢复血管对乙酰胆碱的血管舒张反应。在APN-/-血管中，eNOS表达正常，但NO生成和eNOS磷酸化显著降低（P<0.01）。在体内用脂联素球形结构域处理APN-/-小鼠，可以减少主动脉超氧化物的产生，增加eNOS磷酸化，并使乙酰胆碱的血管舒张反应正常化。当APN生成不足时，一氧化氮失活的增加和基础一氧化氮生成的减少有助于内皮功能障碍的发展。针对提高血浆APN水平的干预措施可能改善内皮功能，减少糖尿病患者的心血管并发症。
Endothelial dysfunction is the earliest pathologic alteration in diabetic vascular injury and plays a critical role in the development of atherosclerosis. Plasma levels of adiponectin (APN), a novel vasculoprotective adipocytokine, are significantly reduced in diabetic patients, but its relationship with endothelial dysfunction remains unclear. The present study aims to determine whether APN deficiency may cause endothelial dysfunction and to investigate the involved mechanisms. Vascular rings were made from the aortic vessels of wild type (WT) or APN knockout (APN-/-) mice. Endothelial function, total NO production, eNOS expression/phosphorylation, superoxide production, and peroxynitrite formation were determined. ACh and acidified NaNO2 (endothelial dependent and independent vasodilators, respectively) caused similar concentration-dependent vasorelaxation in WT vascular rings. APN-/- rings had a normal response to acidified NaNO2, but a markedly reduced response to ACh (>50% reduction vs. WT, P<0.01). Both superoxide and peroxynitrite production were increased in APN-/- vessels (P<0.01 vs. WT). Pretreatment with superoxide scavenger Tiron significantly, but incompletely restored vascular vasodilatory response to ACh. In APN-/- vessels, eNOS expression was normal, but NO production and eNOS phosphorylation was significantly reduced (P<0.01 vs. WT). Treatment of APN-/- mice in vivo with the globular domain of adiponectin reduced aortic superoxide production, increased eNOS phosphorylation, and normalized vasodilatory response to ACh. Increased NO inactivation combined with decreased basal NO production contribute to endothelial dysfunction development when there is a paucity of APN production. Interventions directed towards increasing plasma APN levels may improve endothelial function, and reduce cardiovascular complications suffered by diabetic patients.
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