Lovastatin Inhibition Of Bone Marrow Mesenchymal Stem Cell Apoptosis And Its Signal Transduction Mechanism

Cell therapy with bone marrow-derived mesenchymal stem cells (MSCs) hasbeen shown to have great promises in cardiac repair after myocardial infarction.However, poor viability of transplanted MSCs in the infarcted heart has limited thetherapeutic efficacy. Our previous studies have shown in vitro that rat MSCs undergocaspase-dependent apoptosis in response to hypoxia and serum deprivation(Hypoxia/SD). Recent findings have implicated statins, an established class ofcholesterol-lowering drugs, enhance the survival of cells under various conditions. Inthis study, we investigated the effect of lovastatin on rat MSC apoptosis induced byHypoxia/SD, focusing in particular on regulation of mitochondrial apoptotic pathwayand the survival signaling pathways. We demonstrated that lovastatin (0.01-1μM)remarkably prevented MSCs from Hypoxia/SD-induced apoptosis through inhibitionof the mitochondrial apoptotic pathway, leading to attenuation of caspase-3 activation.The loss of mitochondrial membrane potential and cytochrome c release frommitochondria to cytosol were significantly inhibited by lovastatin. Furthermore, theanti-apoptotic effect of lovastatin on mitochondrial apoptotic pathway was effectivelyabrogated by both PI3K inhibitor, LY294002 and ERK1/2 inhibitor, U0126. Thephosphorylations of Akt/GSK3βand ERK 1/2 stimulated by lovastatin were detected.The activation of ERK1/2 was inhibited by a PI3K inhibitor, LY294002, but U0126, aERK1/2 inhibitor didn't inhibit phosphorylations of Akt and GSK3β. These datademonstrate that lovastatin protects MSCs from Hypoxia/SD-induced apoptosis viaPI3K/Akt and MEK/ERK1/2 pathways, suggesting that it may prove a usefultherapeutic adjunct for transplanting MSCs into damaged heart after myocardialinfarction. This study examined the hypertrophic effect of mesenchymal stemcells-conditioned medium (MSCs-CM) on neonatal rat cardiomyocytes. Rat MSCswere cultured with serum-free medium under hypoxic condition for 3h, 6h, 9h and24h, and then the conditioned medium were collected separately. Cultured neonate ratcardiomyocytes were examined by ~3[H]-Leucine incorporation, ANF-luciferaseexpression, F-actin staining and cell area measurement after stimulated with the aboveMSCs-CM for 48 hours. Compared with control group, the total protein content,3H-leucine incorporation, ANF-luciferase expression and cell area were obviouslyincreased in MSCs-CM stimulated groups. These results demonstrated that MSCs-CMinduced cardiomyocyte hypertrophy in a paracrine manner and implied that this effectlikely involved in the improvement of heart function after MSCs transplantation.