Combined Therapy With Simvastatin and Bone Marrow–Derived Mesenchymal Stem Cells Increases Benefits in Infarcted Swine Hearts

Abstract

Objective-Widespread death of implanted cells hampers stem cell therapy for acute myocardial infarction (AMI). Based on the pleiotropic beneficial effects of statins, we examined whether simvastatin (SIMV) increased the efficacy of mesenchymal stem cell (MSC) transplantation after AMI. Methods and Results-Chinese miniswine (nϭ28) were randomized to 1 of 4 groups (nϭ7 per group): control, SIMV (0.25 mg/kg ⅐ d), MSC transplantation, and SIMVϩMSCs. AMI was created by ligating the left anterior descending coronary artery; MSCs were injected immediately into the cyanotic myocardium. At 6 weeks, MRI showed the number of dyskinetic segments and the infarct size were significantly decreased in the SIMV group. Cardiac function improved and the perfusion defect decreased significantly in the SIMVϩMSC group but not in the MSC-only group (PϽ0.05, versus control group). MSC survival and differentiation were significantly better in the combination group than in the MSC-only group (PϽ0.01). Cell apoptosis decreased significantly in both the SIMV and the SIMVϩMSC groups but not in the MSC-only group when compared with controls (PϽ0.05). Furthermore, oxidative stress and inflammatory response was significantly reduced in the infarcted regions in both the SIMV and the SIMVϩMSCs groups. Conclusions-SIMV treatment improves the therapeutic efficacy of MSC transplantation in acutely infarcted hearts by promoting cell survival and cardiovascular differentiation.

Efficacy of Atorvastatin combined with adipose-derived mesenchymal stem cell transplantation on cardiac function in rats with acute myocardial infarction

“…Our present results revealed that, compared with vehicle administration, 14 days of 10 mg/ kg/day Ator administration could not only decrease inflammatory cells infiltration, myeloperoxidase activity, the expression of inflammatory cytokine mRNA, and regulation of anti-and pro-apoptotic cytokines expression, but also improve cardiac function, as reflected by LVEF and CO elevation, and LVVs and HR reduction in the three Ator groups. Compared with the studies by Yang et al [11,19], there were some discrepancies needed to be addressed. First, the experimental model used by Yang was created by an ischemia-reperfusion procedure, while ours was permanent ligation of coronary artery.…”

“…Therefore, to provide support for the ability of transplanted cells to withstand the hostile microenvironment is an essential prerequisite for cardiac function improvement with MSCs transplantation. Yang et al [11,19] showed that Ator and simvastatin could improve MSCs' cardiac protection efficacy through amelioration of the cardiac milieu in an ischemic-reperfusion injury model. Ator and simvastatin are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, with pleiotropic effects including anti-inflammatory activities, anti-oxidant properties, regulation of pro-and anti-apoptotic cytokine expression, protection of the endothelium, and regulation of endothelial progenitor cell migration and Figure 3 Evaluation of cardiac microenvironment parameters (A) A large number of inflammatory cells infiltrating in peri-infarct areas, and the number of inflammatory cells was less in the three Ator groups than in the control group.…”

Neuroprotective Role of Statins in Alzheimer`s Disease: Anti-Apoptotic Signaling~!2009-02-06~!2010-04-04~!2010-06-22~!

“…It is likely that statins could potentiate the activation of many pro-survival pathways, however, the activation of only a few pro-survival pathways have been demonstrated in neuronal systems [73]. Other pro-survival activation has been demonstrated using cardiac and stem cells [74]. Fig.…”

Autophagy Activation: A Novel Mechanism of Atorvastatin to Protect Mesenchymal Stem Cells from Hypoxia and Serum Deprivation via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

“…They can not only attenuate the inflammation and oxidative stress to provide a better microenvironment for implanted MSCs after AMI, but also increase the anti-apoptotic capacity of MSCs itself under H/SD condition, of which, both make statins a convincing candidate to deal with the ''low survival'' problem of MSCs mentioned previously [3,[13][14][15]. Several signaling pathways have been implicated in this protective role of statins, including AMP-activated protein kinase (AMPK), Janus kinase/ signal transducers and activators of the transcription, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ ERK1/2) pathways [13,14,16].…”