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Published on: June 3, 2018
ML216 Alleviates Age-Related Cardiac Fibrosis by Suppressing TGF-β1 Signaling Pathway
Wenbin Liu1, Feng Cui1, Xiaodan Huang1
1State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Abstract:
Cardiac fibrosis is a hallmark of cardiac aging and a major contributor to development of heart failure. However, therapeutic strategies that specifically target cardiac fibrosis remain limited. In this study, we demonstrate that small-molecule compound ML216 exerts protective effects against aging-associated or β-adrenoceptor agonist isoproterenol-induced cardiac fibrosis in vitro or in vivo. Mechanistically, ML216 inhibits transforming growth factor-β1 (TGF-β1) signaling by reducing TGF-β1 protein levels, thereby attenuating Mothers against decapentaplegic homolog (SMAD) phosphorylation and downstream induction of connective tissue growth factor (CTGF). This leads to a marked suppression of fibrotic genes Col1a1, Cnn2, and Acta2, ultimately resulting in reduced fibrosis. Additionally, the inhibition of the TGF-β1 pathway alleviates cardiomyocytes apoptosis, which may further limit inflammatory responses and contributes to the overall attenuation of cardiac fibrosis. Collectively, these findings demonstrate that ML216 mitigates cardiac fibrosis through the inhibition of TGF-β1 pathway-mediated fibrotic signaling and apoptosis, highlighting its potential as a therapeutic candidate for the treatment of cardiac fibrosis.
Insights
Small molecule ML216 effectively reduces cardiac fibrosis by inhibiting transforming growth factor-β1 (TGF-β1) signaling. This compound shows promise for treating age-related heart conditions and preventing heart failure.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Molecular Medicine
Background:
- Cardiac fibrosis is a key factor in cardiac aging and heart failure development.
- Current therapeutic options for cardiac fibrosis are limited.
- Identifying novel therapeutic targets is crucial for managing fibrotic heart disease.
Purpose of the Study:
- To investigate the antifibrotic effects of small-molecule compound ML216.
- To elucidate the molecular mechanisms underlying ML216's action on cardiac fibrosis.
- To evaluate ML216's therapeutic potential in aging-associated and induced cardiac fibrosis models.
Main Methods:
- In vitro and in vivo studies using aging and isoproterenol-induced cardiac fibrosis models.
- Assessment of transforming growth factor-β1 (TGF-β1) signaling pathway components.
- Analysis of fibrotic gene expression (Col1a1, Cnn2, Acta2) and cardiomyocyte apoptosis.
Main Results:
- ML216 significantly reduced cardiac fibrosis in both aging and induced models.
- ML216 inhibited TGF-β1 signaling by decreasing TGF-β1 levels and SMAD phosphorylation.
- ML216 suppressed downstream fibrotic markers (CTGF) and fibrotic genes, and reduced cardiomyocyte apoptosis.
Conclusions:
- ML216 demonstrates potent antifibrotic effects by inhibiting the TGF-β1 pathway.
- ML216 mitigates cardiac fibrosis by suppressing fibrotic signaling and cardiomyocyte apoptosis.
- ML216 represents a promising therapeutic candidate for treating cardiac fibrosis and related heart conditions.
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