Nox2 mediates high fat high sucrose diet-induced nitric oxide dysfunction and inflammation in aortic smooth muscle cells.
Nox2 mediates high fat high sucrose diet-induced nitric oxide dysfunction and inflammation in aortic smooth muscle cells.
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DOI：
10.1016/j.yjmcc.2014.02.019
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发表时间：
2014-07
影响因子：
5
通讯作者：
Tong, Xiaoyong
中科院分区：
文献类型：
--
作者：
Qin, Zhexue;Hou, Xiuyun;Weisbrod, Robert M.;Seta, Francesca;Cohen, Richard A.;Tong, Xiaoyong
关键词：
饮食诱导的肥胖和代谢综合征是心血管疾病的重要诱因。血管内皮细胞一氧化氮（NO）活性的降低和平滑肌细胞（SMC）对NO反应性的减弱是导致动脉粥样硬化和血管成形术后再狭窄等血管病变的重要原因。肌浆网/内质网Ca ~（2+）ATP酶（SERCA）是内皮细胞和平滑肌细胞NO功能的重要调节因子，其不可逆氧化损伤了NO对SERCA的刺激作用。我们采用高脂高糖饮食（HFHSD）饲养C57 BL/6 J小鼠，研究了SMC SERCA在饮食诱导的肥胖和代谢综合征中的作用。我们发现，HFHSD上调Nox 2 NADPH氧化酶，诱导炎症，增加不可逆的SERCA氧化，并抑制主动脉SERCA的反应NO。培养的主动脉平滑肌细胞从小鼠喂养HFHSD显示增加活性氧的产生，Nox 2上调，不可逆的SERCA氧化，炎症，和NO抑制SMC迁移的能力下降。野生型SERCA 2b的过表达或Nox 2的下调恢复了从HFHSD-fed小鼠分离的SMC中NO介导的迁移抑制。此外，肿瘤坏死因子α（TNFα）增加Nox 2，从而诱导SERCA氧化和炎症。因此，HFHSD诱导的Nox 2在调控SMC对NO和TNFα介导的炎症反应中发挥重要作用，这可能与饮食诱导的肥胖和代谢综合征的心血管疾病的发生发展有关。
Diet-induced obesity and metabolic syndrome are important contributors to cardiovascular diseases. The decreased nitric oxide (NO) bioactivity in endothelium and the impaired response of smooth muscle cell (SMC) to NO significantly contribute to vascular pathologies, including atherosclerosis and arterial restenosis after angioplasty. Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) is an important mediator of NO function in both endothelial cells and SMCs, and its irreversible oxidation impair its stimulation by NO. We used C57BL/6J mice fed a high fat, high sucrose diet (HFHSD) to study the role of SMC SERCA in diet-induced obesity and metabolic syndrome. We found that HFHSD upregulated Nox2 based NADPH oxidase, induced inflammation, increased irreversible SERCA oxidation, and suppressed the response of aortic SERCA to NO. Cultured aortic SMCs from mice fed HFHSD showed increased reactive oxygen species production, Nox2 upregulation, irreversible SERCA oxidation, inflammation, and a decreased ability of NO to inhibit SMC migration. Overexpression of wild type SERCA2b or downregulation of Nox2 restored NO-mediated inhibition of migration in SMCs isolated from HFHSD-fed mice. In addition, tumor necrosis factor alpha (TNFα) increased Nox2 which induced SERCA oxidation and inflammation. Taken together, Nox2 induced by HFHSD plays significant roles in controlling SMC responses to NO and TNFα-mediated inflammation, which may contribute to the development of cardiovascular diseases in diet-induced obesity and metabolic syndrome.
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