Transforming Growth Factor-Beta Receptor Iii Is A Potential Regulator Of Ischemia- Induced Cardiomyocyte Apoptosis

Background-Myocardial 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-beta receptor III (TGF beta R3) on cardiomyocyte apoptosis during MI.Methods and Results-An MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFbR3, 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 TGF beta R3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGF beta R3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFbR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGF beta R3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGF beta R3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFbR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGF beta R3 by adeno-associated viral vector serotype 9-TGF beta R3 short hairpin RNA attenuated the effects of MI in mice.Conclusions-TGF beta R3 promotes apoptosis of cardiomyocytes via a p38 pathway-associated mechanism, and loss of TGFbR3 reduces MI injury, which suggests that TGF beta R3 may serve as a novel therapeutic target for MI.