Background and Purpose Statins decrease heart disease risk, but their mechanisms are not completely understood. We examined the role of the TGF‐β receptor III (TGFBR3) in the inhibition of cardiac fibrosis by simvastatin. Experimental Approach Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice given simvastatin orally for 7 days. Cardiac fibrosis was measured by Masson staining and electron microscopy. Heart function was evaluated by echocardiography. Signalling through TGFBR3, ERK1/2, JNK and p38 pathways was measured using Western blotting. Collagen content and cell viability were measured in cultures of neonatal mouse cardiac fibroblasts (NMCFs). Interactions between TGFBR3 and the scaffolding protein, GAIP‐interacting protein C‐terminus (GIPC) were detected using co‐immunoprecipitation (co‐IP). In vivo, hearts were injected with lentivirus carrying shRNA for TGFBR3. Key Results Simvastatin prevented fibrosis following MI, improved heart ultrastructure and function, up‐regulated TGFBR3 and decreased ERK1/2 and JNK phosphorylation. Simvastatin up‐regulated TGFBR3 in NMCFs, whereas silencing TGFBR3 reversed inhibitory effects of simvastatin on cell proliferation and collagen production. Simvastatin inhibited ERK1/2 and JNK signalling while silencing TGFBR3 opposed this effect. Co‐IP demonstrated TGFBR3 binding to GIPC. Overexpressing TGFBR3 inhibited ERK1/2 and JNK signalling which was abolished by knock‐down of GIPC. In vivo, suppression of cardiac TGFBR3 abolished anti‐fibrotic effects, improvement of cardiac function and changes in related proteins after simvastatin. Conclusions and Implications TGFBR3 mediated the decreased cardiac fibrosis, collagen deposition and fibroblast activity, induced by simvastatin, following MI. These effects involved GIPC inhibition of the ERK1/2/JNK pathway.

Bone marrow mesenchymal stem cells (BMSCs) have been shown to offer a wide variety of cellular functions including the protective effects on damaged hearts. Here we investigated the antiaging properties of BMSCs and the underlying mechanism in a cellular model of cardiomyocyte senescence and a rat model of aging hearts. Neonatal rat ventricular cells (NRVCs) and BMSCs were cocultured in the same dish with a semipermeable membrane to separate the two populations. Monocultured NRVCs displayed the senescence-associated phenotypes, characterized by an increase in the number of b-galactosidase-positive cells and decreases in the degradation and disappearance of cellular organelles in a time-dependent manner. The levels of reactive oxygen species and malondialdehyde were elevated, whereas the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase were decreased, along with upregulation of p53, p21 Cip1/Waf1 , and p16INK4a in the aging cardiomyocytes. These deleterious alterations were abrogated in aging NRVCs cocultured with BMSCs. Qualitatively, the same senescent phenotypes were consistently observed in aging rat hearts. Notably, BMSC transplantation significantly prevented these detrimental alterations and improved the impaired cardiac function in the aging rats. In summary, BMSCs possess strong antisenescence action on the aging NRVCs and hearts and can improve cardiac function after transplantation in aging rats. The present study, therefore, provides an alternative approach for the treatment of heart failure in the elderly population. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:494-502 SIGNIFICANCEThis study demonstrates that bone marrow mesenchymal stem cells show antisenescence action on aging neonatal rat ventricular cells and heart and improve cardiac function in aging rats. The results provide a novel strategy for retarding the cardiac aging process in physiology and abnormal conditions or pathology. This study also provides an alternative approach for treatment of heart failure in the elderly population.

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BackgroundMyocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor‐β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.Methods and ResultsAn MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFβR3, and mitogen‐activated protein kinase signaling were assessed by methylthiazolyldiphenyl‐tetrazolium bromide assay, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFβR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFβR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFβR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFβR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFβR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFβR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFβR3 by adeno‐associated viral vector serotype 9–TGFβR3 short hairpin RNA attenuated the effects of MI in mice.Conclusions TGFβR3 promotes apoptosis of cardiomyocytes via a p38 pathway–associated mechanism, and loss of TGFβR3 reduces MI injury, which suggests that TGFβR3 may serve as a novel therapeutic target for MI.