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.

Activation of Liver X Receptor Improves Viability of Adipose-Derived Mesenchymal Stem Cells to Attenuate Myocardial Ischemia Injury Through TLR4/NF-κB and Keap-1/Nrf-2 Signaling Pathways

“…To clarify this, we used BLI to track engrafted AD-MSCs and showed that most of the implanted AD-MSCs underwent acute cell death in the infarcted myocardium within 7 days, which was similar with prevailing research (41). Our previous studies also found that a higher dosage of stem cells could not avoid acute loss and apoptosis after delivery (2).…”

“…Our data support the hypothesis that LXR agonist attenuates the inflammatory response in AD-MSCs under hypoxic conditions, and prevents oxidative stress induced by hypoxia injury through decreasing gp91 phox expression. As for the differentiation ability of transplanted AD-MSCs, our previous studies showed that transplanted MSCs rarely differentiated into cardiomyocytes in vivo (7,41). Other literature put forward the debate of whether implanted MSCs possess beneficial multipotent differentiation ability in infarcted myocardium (1).…”

“…AD-MSCs were stimulated with H/SD injury as previously described (41). Briefly, AD-MSCs were plated in 24-well plates (5 · 10 4 cells per well).…”

“…However, low retention and poor survival of injected stem cells are major obstacles to achieve intended therapeutic effect. Our previous studies revealed that nearly 90% of the stem cells might not survive within the first 4 days after cell delivery because of ischemia and local inflammation (6,41). Other studies demonstrated that improving the conditions of this unfavorable niche in infarcted myocardium could increase the survival of injected stem cells (31,39).…”

Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

“…The relevance of ERK and AKT signaling for CSC self-renewal and survival has been previously demonstrated. Activation of these pathways by stem cell preconditioning also improves survival after transplantation (48,49). Overexpression of nuclear-targeted AKT in mice induces an increase in the number of myocyte-committed ckit + progenitor cells, with activation of AKT being associated with upregulation of myocardial expression of several growth factor receptor systems known to promote growth and survival (50).…”