Department of Cardiology, FuWai Hospital and Cardiovascular Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, 167 Beilishi Rd, Beijing 100037, People's Republic of China.
Int J Cardiol. 2011 Dec 15;153(3):311-6. doi: 10.1016/j.ijcard.2010.08.047. Epub 2010 Sep 15.
Mesenchymal stem cells (MSCs) are the optimal candidate of treating myocardial infarction; however, the lower survival ratio of implanted cell discourages the advantages of this treatment. Recent studies have displayed statins, which exert pleiotropic effects on the cardiovascular system partially through the increase in endothelial nitric oxide synthase (eNOS) activity, could increase the livability of cells under hypoxia and serum-free (H/SF) conditions. AMP-activated protein kinase (AMPK) is the essential part in keeping the balance of energy production and metabolism in various tissues, which is the dominant factor modulating the programmed cell death. Therefore, we hypothesized that atorvastatin could protect MSCs from H/SF injury through AMPK-eNOS pathway.
Stained with Annexin V/propidine iodine (PI), we found atorvastatin (0.001 μM-10 μM) reduced apoptosis of porcine bone marrow-derived MSCs cultured in H/SF condition; however, this effect was obstructed by compound C, an inhibitor of AMPK. This trend was similar as what bax protein, a pro-apoptosis protein, showed analyzed by Western blotting; whereas the bcl-2 protein, an anti-apoptosis protein, increased in atorvastatin treated cells. Meanwhile, MSCs treated with atorvastatin increased phosphorylation of AMPK and eNOS. The uptrend was partially inhibited by compound C.
Atorvastatin can activate AMPK and the phosphorylation of AMPK results in eNOS activated, which provides a novel explanation for the multi-effect of statins on cardiovascular system.
间充质干细胞（MSCs）是治疗心肌梗死的最佳候选细胞；然而，植入细胞的存活率较低，这降低了这种治疗方法的优势。最近的研究表明，他汀类药物通过增加内皮型一氧化氮合酶（eNOS）的活性对心血管系统发挥多种作用，可提高细胞在缺氧和无血清（H/SF）条件下的存活率。AMP 激活的蛋白激酶（AMPK）是维持各种组织中能量产生和代谢平衡的重要组成部分，是调节细胞程序性死亡的主要因素。因此，我们假设阿托伐他汀可以通过 AMPK-eNOS 途径保护 MSCs 免受 H/SF 损伤。
用 Annexin V/碘化丙啶（PI）染色，我们发现阿托伐他汀（0.001 μM-10 μM）可减少在 H/SF 条件下培养的猪骨髓来源 MSCs 的凋亡；然而，这种作用被 AMPK 的抑制剂 Compound C 阻断。Western blot 分析显示 bax 蛋白（一种促凋亡蛋白）的趋势与这一趋势相似；而抗凋亡蛋白 bcl-2 在阿托伐他汀处理的细胞中增加。同时，阿托伐他汀处理的 MSCs 增加了 AMPK 的磷酸化和 eNOS。这种上升趋势部分被 Compound C 抑制。
阿托伐他汀可以激活 AMPK，而 AMPK 的磷酸化导致 eNOS 激活，这为他汀类药物对心血管系统的多效性提供了新的解释。
