Abstract
The poor survival of stem cells seriously limits their therapeutic efficacy for myocardial infarction (MI). Mineralocorticoid receptor (MR) activation plays an important role in the pathogenesis of multiple cardiovascular diseases. Here, we examined whether MR silencing in bone marrow derived mesenchymal stem cells (MSCs) could improve MSCs’ survival and enhance their cardioprotective effects in MI. MSCs from male Sprague‐Dawley rats were transfected with adenoviral small interfering RNA to silence MR (siRNA‐MR). MR silencing decreased hypoxia‐induced MSCs’ apoptosis, as demonstrated by Annexin V/7‐AAD staining. The mechanisms contributing to the beneficial effects of MR depletion were associated with inhibiting intracellular reactive oxygen species production and increased Bcl‐2/Bax ratio. In vivo study, 1 × 106 of MSCs with or without siRNA‐MR were injected into rat hearts immediately after MI. Depletion of MR could improve the MSCs’ survival significantly in infarcted myocardium, associated with more cardiac function improvement and smaller infarct size. Capillary density were also significantly higher in siRNA group with increased expression of vascular endothelial growth factor. Our study demonstrated that silencing MR promoted MSCs’ survival and repair efficacy in ischaemic hearts. MR might be a potential target for enhancing the efficacy of cell therapy in ischaemic heart disease.
Highlights
Despite the dramatic advances in therapeutic interventions for acute myocardial infarction (AMI), The occurrence of heart failure (HF) after AMI remains the main cause of morbidity and mortality worldwide.[1,2] As a result of a limited regenerative ability, massive and irreversible loss of cardiomyocytes, followed by the progressiveXinxing Xie and Yunli Shen contribution to this work.ventricular remodelling is the key problem of HF complicating AMI.[3]
The male mesenchymal stem cells (MSCs) were used for the following two‐part experiments as previously described[27]: (a) Gender‐mismatched transplantation for quantifying survival MSCs by real‐time PCR (n = 3/group) and fluorescent microscopy (n = 3/ group): 1.0 × 106 of MSCs transfected with AAV‐NC‐siRNA (NC group) or AAV‐Mineralocorticoid receptor (MR)‐siRNA in 100 μL of volume were intramyocardially injected at four sites into female recipient hearts; (b) Gender‐matched transplantation for cardiac function comparison: 1.0 × 106 of MSCs transfected with AAV‐NC‐siRNA (NC group) or AAV‐MR‐siRNA or PBS (PBS group) in 100 μL of volume were intramyocardially injected at four sites into the anterior and lateral aspects of the viable myocardium bordering the infarction of male Sprague‐Dawley rats hearts immediately after AMI with a 30‐gauge needle (n = 5/group)
Promoting MSCs’ survival was more attractive than increasing MSCs quantity in order to improve the cardiac repair capacity of MSCs, considering the results of clinical trials which found a higher number of injected cells could potentially damage the cardiac function.[14]
Summary
Despite the dramatic advances in therapeutic interventions for acute myocardial infarction (AMI), The occurrence of heart failure (HF) after AMI remains the main cause of morbidity and mortality worldwide.[1,2] As a result of a limited regenerative ability, massive and irreversible loss of cardiomyocytes, followed by the progressive. Therapy in AMI,[5-8] and its improvement in cardiac function is comparable with the results from reperfusion and pharmacological therapy.[9]. Recent clinical trials observed a direct relationship between dose and efficacy in cell therapy for ischaemic heart disease.[10-12]. Considering a “ceiling effect” of cell therapy for heart disease,[14] it was a more attractive strategy to promote the MSCs’ survival when compared with unlimited increase in MSCs’ dose to enhance the therapeutic efficacy of stem cell therapy. As two important hormone ligands, aldosterone and corticosterone plasma levels were elevated after infarction, MR antagonists or MR deletion could suppress cardiomyocytes apoptosis and prevent adverse cardiac remodelling after AMI.[18,19]. Previous studies revealed that MR activation by aldosterone could impair the function and decrease the number of endothelia progenitor cells (EPCs).[21]. We hypothesized that MR might be involved in the process of MSCs’ apoptosis after transplantation in AMI, and this study was conducted to verify this hypothesis
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