The cardioprotective effect of a statin and cilostazol combination: Relationship to akt and endothelial nitric oxide synthase activation
The cardioprotective effect of a statin and cilostazol combination: Relationship to akt and endothelial nitric oxide synthase activation
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DOI：
10.1007/s10557-007-6036-0
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发表时间：
2007-10-01
影响因子：
3.4
通讯作者：
Birnbaum, Yochai
中科院分区：
文献类型：
--
作者：
Manickavasagam, Saraswathy;Ye, Yumei;Birnbaum, Yochai
背景阿托伐他汀（ATV）通过上调Akt和随后的内皮型一氧化氮合酶（eNOS）Ser-1177磷酸化来保护缺血再灌注。然而，当口服给药时，需要高剂量的ATV（10 mg/kg/d）才能在大鼠中达到最大的保护作用。蛋白激酶A（PKA）也在Ser-1177处磷酸化eNOS。由于PKA活性取决于cAMP，西洛他唑（CIL）是一种III型磷酸二酯酶抑制剂，可能会通过激活PKA来刺激NO的产生。假设：方法Sprague-Dawley大鼠经口给予以下预处理：（1）水;（2）低剂量ATV（2 mg/kg/d）;（3）CIL（20 mg/kg/d）;（4）ATV+CIL。大鼠进行30分钟的冠状动脉闭塞和4小时的再灌注，或心脏移植免疫印迹没有受到缺血。结果各组大鼠的体重和AR的大小无显著性差异。各组间平均血压和心率无显著差异。CIL，而不是ATV，减少IS。ATV+CIL组的IS显著小于其他三组（每次比较P < 0.001）。ATV、CIL及其联合应用对eNOS表达无明显影响。2 mg/kg/d的ATV未影响Ser-1177 P-eNOS水平，而CIL增加了该水平（258 +/- 15%）。ATV+CIL组心肌P-eNOS水平最高（406 ± 7%）。结论ATV和CIL对eNOS磷酸化和IS降低具有协同作用。通过增加eNOS的激活，CIL可能增强他汀类药物的多效性作用。
Background Atorvastatin (ATV) protects against ischemia-reperfusion by upregulating Akt and subsequently, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177. However, when given orally, high doses of ATV (10 mg/kg/d) are needed to achieve maximal protective effect in the rat. Protein kinase A (PKA) also phosphorylates eNOS at Ser-1177. As PKA activity depends on cAMP, cilostazol (CIL), a phosphodiesterase type III inhibitor, may stimulate NO production by activating PKA. Hypothesis: CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size ( IS) reduction.Methods Sprague-Dawley rats received 3-day oral pretreatment with: (1) water; (2) low dose ATV (2 mg/kg/d); (3) CIL (20 mg/kg/d): (4) ATV+CIL. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts explanted for immunoblotting without being subjected to ischemia. Area at risk (AR) was assessed by blue dye and IS by triphenyl-tetrazolium-chloride.Results Body weight and the size of AR were comparable among groups. There were no significant differences among groups in mean blood pressure and heart rate. CIL, but not ATV, reduced IS. IS in the ATV+CIL group was significantly smaller than the other three groups (P < 0.001 for each comparison). ATV, CIL and their combination did not affect total eNOS expression. ATV at 2 mg/kg/d did not affect Ser-1177 P-eNOS levels, whereas CIL increased it (258 +/- 15%). The level of myocardial P-eNOS levels was highest in the ATV+CIL group (406 +/- 7%).Conclusions ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.