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Published on: June 3, 2018
Transforming Growth Factor-β Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis
Fei Sun1, Xin Li1, Wen-Qi Duan1
1Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
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-β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.
Methods And Results:
An 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.
Insights
Transforming growth factor-β receptor III (TGFβR3) promotes cardiomyocyte apoptosis through the p38 pathway, increasing myocardial infarction (MI) injury. Loss of TGFβR3 reduces MI damage, suggesting it as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Molecular Medicine
Background:
- Myocardial infarction (MI) often leads to cardiomyocyte apoptosis, impairing heart function and increasing heart failure risk.
- Transforming growth factor-β receptor III (TGFβR3) role in cardiomyocyte apoptosis during MI requires elucidation.
Purpose of the Study:
- To investigate the effects of TGFβR3 on cardiomyocyte apoptosis in the context of MI.
- To explore the underlying molecular mechanisms, particularly the involvement of mitogen-activated protein kinase (MAPK) signaling pathways.
Main Methods:
- Established a myocardial infarction mouse model using left anterior descending coronary artery ligation.
- Assessed cell viability, apoptosis, TGFβR3 expression, and MAPK signaling (p38, ERK1/2, JNK1/2) using various biochemical and imaging techniques.
- Utilized in vitro cell culture and in vivo genetic manipulation (transgenic mice, shRNA) to modulate TGFβR3 levels.
Main Results:
- TGFβR3 expression dynamically changed in the heart's border region post-MI.
- TGFβR3 overexpression in cardiomyocytes increased apoptosis and activated p38 signaling; knockdown had opposing effects.
- In vivo, cardiac TGFβR3 overexpression exacerbated MI-induced apoptosis and injury, while TGFβR3 knockdown attenuated these effects, mediated by p38 signaling.
Conclusions:
- TGFβR3 promotes cardiomyocyte apoptosis via a p38 pathway-dependent mechanism.
- Reducing TGFβR3 levels mitigates myocardial infarction injury.
- TGFβR3 represents a potential therapeutic target for managing myocardial infarction.
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