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Transforming Growth Factor-? Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

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

SUBMITTER: Sun F

PROVIDER: S-EPMC5669164 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Transforming Growth Factor-β Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

Sun Fei F Li Xin X Duan Wen-Qi WQ Tian Wei W Gao Ming M Yang Jia J Wu Xia-Yang XY Huang Di D Xia Wei W Han Yan-Na YN Wang Jia-Xin JX Liu Yan-Xin YX Dong Chang-Jiang CJ Zhao Dan D Ban Tao T Chu Wen-Feng WF

Journal of the American Heart Association 20170530 6

<h4>Background</h4>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-β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.<h4>Methods and results</h4>An MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFβR3, and mitogen-activated protein kina ...[more]

PMID: 28559372

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Project description:Transforming growth factor-βs (TGF-βs) regulate cellular proliferation, differentiation, and survival. TGF-βs bind to type I (TGF-βRI) and II receptors (TGF-βRII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-βRIII). TGF-β may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-β is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-β1-3 after MCAO. To establish how TGF-βs exert their actions following MCAO, the present study describes the induction of TGF-βRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-βRI had significant expression: neurons in cortical layer IV contained TGF-βRI. At 24 h after the occlusion, no TGF-β receptors showed induction. At 72 h following MCAO, all four types of TGF-β receptors were induced in the infarct area, while TGF-βRI and RII also appeared in the penumbra. Most cells with elevated TGF-βRI mRNA levels were microglia. TGF-βRII co-localized with both microglial and endothelial markers while TGF-βRIII and Alk1 were present predominantly in endothels. All four TGF-β receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-βRIII was further induced as compared to 72 h after MCAO. At this time point, TGF-βRIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-β receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-β receptor expression is preceded by increased TGF-β expression. TGF-βRI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-βRII, and RIII in endothels within the infarct where TGF-β1 may be their ligand. At later time points, TGF-βRIII may also appear in glial cells to potentially affect signal transduction via TGF-βRI and RII.

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Transforming Growth Factor-? Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

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Transforming Growth Factor-β Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

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