Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis
Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis
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DOI：
10.2337/db15-0472
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发表时间：
2015-11-01
期刊：
影响因子：
7.7
通讯作者：
Bernatchez, Pascal
中科院分区：
文献类型：
--
作者：
Sharma, Arpeeta;Sellers, Stephanie;Bernatchez, Pascal
糖尿病患者发生动脉粥样硬化的风险增加。内皮功能障碍，以内皮NO合成酶（eNOS）衍生NO的生物利用度降低为特征，是动脉粥样硬化的关键诱导剂。然而，eNOS在糖尿病相关动脉粥样硬化中的保护作用仍然存在争议，这可能是其在正常和疾病环境下分别释放保护性NO或有害氧自由基的能力的结果。在糖尿病患者中利用eNOS的动脉粥样硬化保护活性仍然难以捉摸，部分原因是缺乏内源性eNOS特异性NO释放激活剂。我们最近在体外表明，通过使用高度特异性的肽CavNOxin阻断其与Caveolin-1（小窝的主要外壳蛋白）的结合，可以增加enos衍生的NO的释放。然而，使用这种肽靶向eNOS是否可以减轻糖尿病相关动脉粥样硬化尚不清楚。在这项研究中，我们发现CavNOxin在体内可以减轻动脉粥样硬化负担，约为84%。相比之下，缺乏eNOS的小鼠对CavNOxin治疗表现出耐药性，表明eNOS特异性。在机制上，CavNOxin降低氧化应激标志物，抑制促动脉粥样硬化介质的表达，阻断白细胞与内皮细胞的相互作用。这些数据首次表明内源性eNOS激活可以在糖尿病中提供动脉粥样硬化保护，并表明CavNOxin是开发抗动脉粥样硬化化合物的可行策略。
Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS-specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by similar to 84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds.