title: Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways.
abstract: 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.
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Zheng
authors: Z
authors: Zhang
authors: Shuang
authors: S
authors: Li
authors: Mingliang
authors: M
authors: Cui
authors: Xue
authors: X
authors: Gao
authors: Dongdong
authors: D
authors: Sun
authors: Xing
authors: X
authors: Qin
authors: Kazim
authors: K
authors: Narsinh
authors: Chunhong
authors: C
authors: Li
authors: Hongbing
authors: H
authors: Jia
authors: Congye
authors: C
authors: Li
authors: Yaling
authors: Y
authors: Han
authors: Haichang
authors: H
authors: Wang
authors: Feng
authors: F
authors: Cao
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D005464:Fluorobenzenes / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism / Q000628:therapy*; D032383:Myocytes, Cardiac; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt