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Published on: June 3, 2018
CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast
Dan Wu1, Hong Lei1, Jin-Yu Wang1
1Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
Unlabelled:
C1q/tumor necrosis factor-related protein-3 (CTRP3) is a novel adipokine with modulation effects on metabolism, inflammation, and cardiovascular system. This study aimed to investigate the effect of CTRP3 on cardiac fibrosis and its underlying mechanism. The myocardial expression of CTRP3 was significantly decreased after myocardial infarction (MI). Adenovirus-delivered CTRP3 supplement attenuated myocardial hypertrophy, improved cardiac function, inhibited interstitial fibrosis, and decreased the number of myofibroblasts post-MI. In cultured adult rat cardiac fibroblasts (CFs), CTRP3 attenuated cell proliferation; migration; and the expression of connective tissue growth factor, collagen I, and collagen III induced by transforming growth factor (TGF)-β1. Moreover, CTRP3 inhibited whereas CTRP3 small interfering RNA (siRNA) facilitated the expression of α-SMA and profibrotic molecules induced by TGF-β1. CTRP3 also attenuated TGF-β1-induced Smad3 phosphorylation, nuclear translocation, and interaction with p300. CTRP3 increased the phosphorylation of AMP-activated protein kinase (AMPK) and Akt in both rat hearts and CFs. Adenine 9-β-D-arabinofuranoside (AraA), an AMPK inhibitor, abolished the protective effect of CTRP3 against TGF-β1-induced profibrotic response and Smad3 activation. Taken together, CTRP3 attenuates cardiac fibrosis by inhibiting myofibroblast differentiation and the subsequent extracellular matrix production. AMPK is required for the anti-fibrotic effect of CTRP3 through targeting Smad3 activation and inhibiting myofibroblast differentiation.
Key Message:
CTRP3 alleviates cardiac fibrosis in a rat post-MI model and in cardiac fibroblasts. CTRP3 inhibits fibroblast-to-myofibroblast differentiation. CTRP3 exerts anti-fibrotic effect through targeting Smad3 activation. AMPK mediates the anti-fibrotic effect of CTRP3 by inhibition of Smad3 activation.
Insights
C1q/tumor necrosis factor-related protein-3 (CTRP3) reduces cardiac fibrosis by inhibiting fibroblast differentiation and extracellular matrix production. This anti-fibrotic effect is mediated by AMP-activated protein kinase (AMPK) targeting Smad3 activation.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Fibrosis Research
Background:
- C1q/tumor necrosis factor-related protein-3 (CTRP3) is an adipokine influencing metabolism and cardiovascular health.
- Cardiac fibrosis, a key factor in heart dysfunction post-myocardial infarction (MI), involves fibroblast activation and extracellular matrix deposition.
- The role of CTRP3 in regulating cardiac fibrosis remains largely unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of CTRP3 in mitigating cardiac fibrosis.
- To elucidate the underlying molecular mechanisms by which CTRP3 affects cardiac fibroblast activation and differentiation.
Main Methods:
- Adenovirus-mediated delivery of CTRP3 in a rat myocardial infarction (MI) model.
- In vitro studies using cultured adult rat cardiac fibroblasts (CFs) treated with transforming growth factor-beta1 (TGF-β1).
- Assessment of cardiac function, fibrosis, myofibroblast markers, extracellular matrix components, and signaling pathways (Smad3, AMPK, Akt).
Main Results:
- CTRP3 supplementation post-MI attenuated cardiac hypertrophy, improved cardiac function, and reduced interstitial fibrosis and myofibroblast accumulation.
- In vitro, CTRP3 inhibited TGF-β1-induced proliferation, migration, and expression of collagen I, collagen III, and alpha-smooth muscle actin (α-SMA) in CFs.
- CTRP3 suppressed TGF-β1-induced Smad3 phosphorylation and nuclear translocation, while activating AMP-activated protein kinase (AMPK) and Akt pathways.
Conclusions:
- CTRP3 effectively alleviates cardiac fibrosis in both in vivo and in vitro models.
- CTRP3 inhibits the differentiation of cardiac fibroblasts into myofibroblasts, thereby reducing extracellular matrix production.
- The anti-fibrotic effects of CTRP3 are mediated through the AMPK pathway, which targets Smad3 activation and suppresses myofibroblast differentiation.
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