4.6 Article

Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway

Journal

INTERNATIONAL JOURNAL OF CARDIOLOGY
Volume 176, Issue 3, Pages 670-679

Publisher

ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2014.07.071

Keywords

Mesenchymal stem cells; Acute myocardial infarction; Atorvastatin; Rho-associated coiled-coil forming kinase; Extracellular regulated protein kinase; Fasudil

Funding

  1. National Natural Science Foundation of China [81000091, 81170129, 81200107]
  2. China Health & Medical Development Foundation [2008-zhfj2]
  3. National High Technology Research and Development Program (863 Program) [2011AA020110]

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Background: Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the pleiotropic effects of station. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo. Methods and results: Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. AN facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. AN inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI. Conclusions: ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation. (C) 2014 Published by Elsevier Ireland Ltd.

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