Endothelial nitric oxide synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation.
Endothelial nitric oxide synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation.
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DOI：
10.3389/fcvm.2023.1279868
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发表时间：
2023
影响因子：
3.6
通讯作者：
Lee, Monica Y.
中科院分区：
文献类型：
--
作者：
Nguyen, Tung D.;Rahman, Nur-Taz;Sessa, William C.;Lee, Monica Y.
我们之前已经证明了Akt-eNOS底物-激酶关系在体内的重要性，因为当与“获得功能”的eNOS S1176D突变小鼠繁殖时，全球akt1缺失小鼠的出生后血管生成特征缺陷被挽救。虽然多项研究支持内皮NO生成的血管保护作用，但akt1依赖性eNOS S1176磷酸化在动脉粥样硬化斑块形成中的因果作用尚不清楚。我们在此培育了基因“功能缺失”的eNOS S1176A和“功能获得”的eNOS S1176D突变小鼠，以加剧动脉粥样硬化的Akt1−/−；ApoE−/−双敲除小鼠，明确测试akt介导的eNOS S1176磷酸化在动脉粥样硬化中的重要性。我们发现，eNOS S1176磷酸化位点的单个氨基酸替换对动脉粥样硬化斑块形成产生不同的影响，因为eNOS S1176磷酸化的模拟天门氨酸(D)替换导致有利的脂质谱和动脉粥样硬化指数下降，即使在促粥样硬化的Akt1全局缺失背景下也是如此。相反，携带丙氨酸（S1176A）不可磷酸化突变的小鼠会导致血脂升高，病变形成和细胞凋亡增加，表型复制eNOS缺失和/或酶功能受损的生理后果。此外，对整个主动脉的基因表达分析表明，一氧化氮缺乏和西方饮食挑战对其造成了组合损害，因为与eNOS S1176D小鼠相比，西方饮食中“功能丧失”的eNOS S1176A小鼠呈现出独特的表达模式，表明t细胞活性增强。通过使用遗传上位性方法，我们最终证明akt介导的eNOS S1176磷酸化和随后的eNOS激活仍然是促进动脉粥样硬化保护作用的NO产生的最生理学相关的方法。
We have previously demonstrated the in vivo importance of the Akt-eNOS substrate-kinase relationship, as defective postnatal angiogenesis characteristic of global Akt1-null mice is rescued when bred to ‘gain-of-function’ eNOS S1176D mutant mice. While multiple studies support the vascular protective role of endothelial NO generation, the causal role of Akt1-dependent eNOS S1176 phosphorylation during atherosclerotic plaque formation is not yet clear. We herein bred congenic ‘loss-of-function’ eNOS S1176A and ‘gain-of-function’ eNOS S1176D mutant mice to the exacerbated atherogenic Akt1−/−; ApoE−/− double knockout mice to definitively test the importance of Akt-mediated eNOS S1176 phosphorylation during atherogenesis. We find that a single amino acid substitution at the eNOS S1176 phosphorylation site yields divergent effects on atherosclerotic plaque formation, as an eNOS phospho-mimic aspartate (D) substitution at S1176 leads to favorable lipid profiles and decreased indices of atherosclerosis, even when on a proatherogenic Akt1 global deletion background. Conversely, mice harboring an unphosphorylatable mutation to alanine (S1176A) result in increased plasma lipids, increased lesion formation and cellular apoptosis, phenocopying the physiological consequence of eNOS deletion and/or impaired enzyme function. Furthermore, gene expression analyses of whole aortas indicate a combinatorial detriment from NO deficiency and Western Diet challenge, as ‘loss-of-function’ eNOS S1176A mice on a Western Diet present a unique expression pattern indicative of augmented T-cell activity when compared to eNOS S1176D mice. By using genetic epistasis approaches, we conclusively demonstrate that Akt-mediated eNOS S1176 phosphorylation and subsequent eNOS activation remains to be the most physiologically relevant method of NO production to promote athero-protective effects.
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DOI：
10.1161/atvbaha.118.311705
发表时间：
2018-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Al-Yafeai Z;Yurdagul A Jr;Peretik JM;Alfaidi M;Murphy PA;Orr AW
通讯作者：
Orr AW
DOI：
10.36922/gtm.v1i1.76
发表时间：
2022-01-01
期刊：
Global translational medicine
影响因子：
--
作者：
Chen, Hui;Howatt, Deborah A;Lu, Hong S
通讯作者：
Lu, Hong S
影响因子：
12.4
作者：
Devey, Luke;Ferenbach, David;Wigmore, Stephen J.
通讯作者：
Wigmore, Stephen J.
DOI：
10.1016/j.bbrc.2012.12.110
发表时间：
2013-02-08
影响因子：
3.1
作者：
Kashiwagi, Satoshi;Atochin, Dmitriy N.;Li, Qian;Schleicher, Michael;Pong, Terrence;Sessa, William C.;Huang, Paul L.
通讯作者：
Huang, Paul L.
影响因子：
37.8
作者：
COSENTINO, F;KATUSIC, ZS
通讯作者：
KATUSIC, ZS