ES cells overexpressing microRNA-1 attenuate apoptosis in the injured myocardium

MicroRNAs (miRs) are small, single-stranded, noncoding RNA’s involved in post-transcriptional negative gene regulation. Recent investigations have underscored the integral role of miRs in various biological processes including innate immunity, cell-cycle regulation, metabolism, differentiation, and cell death. In the present study, we overexpressed miR-1, a muscle-specific miR, in embryonic stem cells (miR-1-ES cells), transplanted them into the infarcted myocardium, and evaluated their impact on cardiac apoptosis and function. We provide evidence demonstrating reduced apoptosis following transplantation of miR-1-ES cells 4 weeks post-myocardial infarction as compared to respective controls assessed by TUNEL staining and a capsase-3 activity assay. Moreover, we show significant elevation in p-Akt levels and diminished PTEN levels in hearts transplanted with miR-1-ES cells as determined by enzyme-linked immunoassays. Finally, using echocardiography, we reveal mice receiving miR-1-ES cell transplantation post-myocardial infarction had significantly improved fractional shortening and ejection fraction compared with respective controls. Our data suggest transplanted miR-1-ES cells inhibit apoptosis, mediated through the PTEN/Akt pathway, leading to improved cardiac function in the infarcted myocardium

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

Abstract Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI

Adipokines and the Right Ventricle: The MESA-RV Study

Obesity is associated with changes in both right (RV) and left (LV) ventricular morphology, but the biological basis of this finding is not well established. We examined whether adipokine levels were associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.We examined relationships of leptin, resistin, TNF-α, and adiponectin with RV morphology and function (from cardiac MRI) in participants (n = 1,267) free of clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of each adipokine with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF).Higher leptin levels were associated with significantly lower levels of RV mass, RVEDV, RVESV and stroke volume, but not RVEF, after adjustment for age, gender, race, height and weight. These associations were somewhat attenuated but still significant after adjustment for traditional risk factors and covariates, and were completely attenuated when correcting for the respective LV measures. There were no significant interactions of age, gender, or race/ethnicity on the relationship between the four adipokines and RV structure or function.Leptin levels are associated with favorable RV morphology in a multi-ethnic population free of cardiovascular disease, however these associations may be explained by a yet to be understood bi-ventricular process as this association was no longer present after adjustment for LV values. These findings complement the associations previously shown between adipokines and LV structure and function in both healthy and diseased patients. The mechanisms linking adipokines to healthy cardiovascular function require further investigation

Stem cells in the diabetic infarcted heart

Diabetes mellitus is one of the leading causes of death, and the majority of these deaths are associated with cardiovascular diseases. Development and progression of myocardial infarction leading to heart failure is much more complex and multifactorial in diabetics compared with non-diabetics. Despite significant advances in pharmacological interventions and surgical techniques, the disease progression leading to diabetic end-stage heart failure remains very high. Recently, cell therapy has gained much attention as an alternative approach to treat various heart diseases. However, transplanted stem cell studies in diabetic animal models are very limited. In this review, we discuss the pathogenesis of the diabetic infarcted heart and the potential of stem cell therapy to repair and regenerate