Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways

被引：118

作者：

Zhang, Zheng ^{[1
]}

Li, Shuang ^{[1
]}

Cui, Mingliang ^{[1
]}

Gao, Xue ^{[2
]}

Sun, Dongdong ^{[1
]}

Qin, Xing ^{[1
]}

Narsinh, Kazim ^{[3
]}

Li, Chunhong ^{[1
]}

Jia, Hongbing ^{[4
]}

Li, Congye ^{[1
]}

Han, Yaling ^{[5
]}

Wang, Haichang ^{[1
]}

Cao, Feng ^{[1
]}

机构：

[1] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiol, Xian 710032, Peoples R China

[2] Mil Gen Hosp Beijing PLA, Dept Ultrasonog, Beijing 100700, Peoples R China

[3] UC San Diego Sch Med, Dept Radiol, La Jolla, CA USA

[4] 323 Hosp PLA, Dept Orthoped, Xian 710054, Peoples R China

[5] Shenyang PLA Gen Hosp, Dept Cardiol, Shenyang, Peoples R China

来源：

BASIC RESEARCH IN CARDIOLOGY | 2013年 / 108卷 / 02期

关键词：

Rosuvastatin; Adipose-derived mesenchymal stem cells; Myocardial infarction; Phosphatidylinositol; 3-kinase; Extracellular signal-regulated kinase; FoxO3a; Apoptosis; BONE-MARROW-CELLS; REDUCTASE INHIBITOR; SURVIVAL PATHWAY; ISCHEMIC-HEART; CYTOCHROME-C; ATORVASTATIN; IMPROVEMENT; DISEASE; PROTEIN; FOXO3A;

D O I：

10.1007/s00395-013-0333-5

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The poor viability of transplanted stem cells hampers their therapeutic efficacy for treatment of myocardial infarction. The aim of this study was to investigate whether rosuvastatin improved survival of adipose-derived mesenchymal stem cells (AD-MSCs) after transplantation into infarcted hearts. AD-MSCs isolated from Tg(Fluc-egfp) mice which constitutively express both firefly luciferase (Fluc) and enhanced green fluorescent protein were transplanted into infarcted hearts with or without rosuvastatin administration. Longitudinal in vivo bioluminescence imaging and histological staining revealed that rosuvastatin enhanced the survival of engrafted AD-MSCs. Furthermore, combined therapy of AD-MSC and rosuvastatin reduced fibrosis, decreased cardiomyocyte apoptosis, and preserved heart function. AD-MSCs were then subjected to hypoxia and serum deprivation injury in vitro to mimic the ischemic environment. Rosuvastatin (10(-6) mmol/L) enhanced the viability and paracrine effect of AD-MSCs, and decreased their apoptotic rate. Western blotting revealed that rosuvastatin supplementation increased Akt and ERK phosphorylation, which resulted in FoxO3a phosphorylation and nuclear export. In addition, rosuvastatin administration decreased the pro-apoptotic proteins Bim and Bax, and increased the anti-apoptotic proteins Bcl-xL and Bcl-2. Furthermore, these effects were abolished by PI3K inhibitor LY294002 and MEK1/2 inhibitor U0126. This study demonstrates that rosuvastatin may improve the survival of engrafted AD-MSCs at least in part through the PI3K/Akt and MEK/ERK1/2 signaling pathways. Combination therapy with rosuvastatin and AD-MSCs has a synergetic effect on improving myocardial function after infarction.

引用

页数：18

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