Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase.
Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase.
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阿托伐他汀通过激活一氧化氮合酶增强间充质干细胞治疗猪心肌梗死的疗效。
DOI：
10.1371/journal.pone.0065702
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gersh BJ
中科院分区：
文献类型：
--
作者：
Song L;Yang YJ;Dong QT;Qian HY;Gao RL;Qiao SB;Shen R;He ZX;Lu MJ;Zhao SH;Geng YJ;Gersh BJ
在猪急性心肌梗死（AMI）模型中，他汀类药物可以提高间充质干细胞（MSCs）移植的治疗效果。然而，其机制尚不清楚。本研究旨在评估阿托伐他汀（Ator）是否通过激活一氧化氮合酶（NOS），特别是内皮型一氧化氮合酶（eNOS）来促进间充质干细胞的作用，而内皮型一氧化氮合酶具有保护缺血性损伤的作用。42例微型小鼠随机分为6组（n = 7/组）：假手术；AMI控制;Ator;采用心内直视手术建立猪冠状动脉结扎再灌注模型，心肌内注射自体骨髓MSCs。移植后4周，与对照组相比，Ator+MSCs动物在单光子发射计算机断层扫描定义的“灌注”（- 6.2±1.8% vs. 2.0±5.1%,P = 0.0001）和正电子发射断层扫描定义的“代谢”（- 3.00±1.41% vs. 4.20±4.09%,P = 0.0004）缺陷面积均有所减少；磁共振射血分数明显升高（14.22±12.8% vs. 1.64±2.64%,P = 0.019）。此外，Ator+MSCs动物的炎症、纤维化和凋亡指标降低，MSCs或MSCs衍生细胞的存活率增加。在Ator或MSCs单独组，灌注、代谢、炎症、纤维化或凋亡减少，但在心功能和细胞存活方面没有益处。此外，Ator+MSCs治疗的上述益处可能被L-NNA部分阻断。阿托伐他汀促进移植间充质干细胞的存活，改善梗死心脏的功能和形态，其作用机制由eNOS激活介导，NOS抑制剂可减轻其作用。这些数据揭示了他汀类药物和干细胞联合抗ami治疗的细胞和分子机制。
In a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury. 42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both “perfusion” defined by Single-Photon Emission Computed Tomography (−6.2±1.8% vs. 2.0±5.1%, P = 0.0001) and “metabolism” defined by Positron Emission Tomography (−3.00±1.41% vs. 4.20±4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22±12.8% vs. 1.64±2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA. Atorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells.
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影响因子：
2.6
作者：
Weir, Christopher;Morel-Kopp, Marie-Christine;Ward, Christopher
通讯作者：
Ward, Christopher
影响因子：
10.8
作者：
Gonon, Adrian T.;Widegren, Ulrika;Pernow, John
通讯作者：
Pernow, John
影响因子：
20.1
作者：
BUXTON, ILO;CHEEK, DJ;KEEF, KD
通讯作者：
KEEF, KD
阿托伐他汀通过激活 AMP 激活的蛋白激酶来防止间充质干细胞缺氧和无血清损伤。
影响因子：
3.5
作者：
Dong, Qiuting;Yang, Yuejin;Xu, Zhimin
通讯作者：
Xu, Zhimin
影响因子：
11.3
作者：
Forrester, James S.;White, Anthony J.;Makkar, Raj R.
通讯作者：
Makkar, Raj R.