Simvastatin increases the activity of endothelial nitric oxide synthase via enhancing phosphorylation
Simvastatin increases the activity of endothelial nitric oxide synthase via enhancing phosphorylation
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DOI：
10.1007/s11596-009-0304-0
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发表时间：
2009-06
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影响因子：
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通讯作者：
Xiaoxia Li;Peihua Wang;Xizhen Xu;Yong Wang;Yong Xia;Daowen Wang
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文献类型：
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作者：
Xiaoxia Li;Peihua Wang;Xizhen Xu;Yong Wang;Yong Xia;Daowen Wang
3-羟基-3-甲基谷氨酰辅酶A(HMG-CoA)还原酶抑制剂或他汀类药物是一种降血脂药物，已被用于心血管疾病的预防和治疗。最近的研究表明，他汀类药物除了降低胆固醇外，还可能通过增强内皮型一氧化氮合酶(ENOS)的活性来保护血管。在本研究中，我们研究了辛伐他汀是否通过其磷酸化增加了293细胞(293-eNOS)中eNOS的活性。结果表明，辛伐他汀(10μm/m in·mg)作用2 h后，eNOS活性显著增加，L-精氨酸转化率为2889.70±201.51，而L-瓜氨酸转化率为5630.18±218.75 pmoL/m in·mg蛋白质。Western blotting显示辛伐他汀可增加eNOS 1177位(Ser)和495位(Thr)的磷酸化，但不影响eNOS或诱导型一氧化氮合酶的整体表达。进一步研究发现，辛伐他汀可提高Akt和AMPK的磷酸化水平，这种作用可被Akt抑制剂或AMPK抑制剂所拮抗。这些结果表明，辛伐他汀可通过Akt和AMPK的磷酸化激活eNOS的活性，这为他汀类药物的心血管保护作用提供了除降脂作用外的新机制。
3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are a kind of lipid-lowering agents and have been used for the prevention and treatment of cardiovascular diseases. Recent studies suggested that statins, besides lowering cholesterol, may protect vessels by enhancing the activity of endothelial nitric oxide synthase (eNOS). In the present study, we investigated if simvastatin increases eNOS activity through its phosphorylation in 293 cells (293-eNOS) with stable expression of eNOS. The results showed that incubation of 293-eNOS cells with simvastatin (10 μm/L) for 2 h significantly increased in the activity of eNOS as shown by the conversion ofL-arginine toL-citrulline (2889.70±201.51 versus 5630.18±218.75 pmol/min · mg proteins) (P<0.01). Western blotting revealed that simvastatin increased phosphorylation of eNOS at 1177 (ser) and also 495 (thr) but did not affect the overall expression of eNOS or inducible NOS. Further study found that simvastatin raised phosphorylation levels of Akt and AMPK, and such effect could be antagonized by Akt inhibitor or AMPK inhibitor. These results suggest that simvastatin could stimulate the activity of eNOS via its phosphorylation by Akt and AMPK, which provides a new mechanism, other than lipid-lowering effect, for the cardiovascular protection of statins.