Dataset Information

Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β-Smad3 Pathway.

ABSTRACT: Follistatin (FST) is an endogenous protein that irreversibly inhibits TGF-β superfamily members and plays an anti-fibrotic role in other diseases. However, the role of FST in diabetic cardiomyopathy remains unclear. In this study, we investigated the effects of FST on diabetic cardiomyopathy. The expression of FST was downregulated in the hearts of db/db mice. Remarkably, overexpressing FST efficiently protected against cardiac dysfunction. In addition, overexpression of FST promoted cardiac hypertrophy with an unchanged expression of atrial natriuretic peptide (ANP) and the ratio of myosin heavy chain-β/myosin heavy chain-α (MYH7/MYH6). Furthermore, FST reduced cardiac fibrosis and the production of reactive oxygen species (ROS), and enhanced matrix metallopeptidase 9 (MMP9) activities in db/db mouse hearts. We also observed that overexpressing FST decreased the level of transforming growth factor beta (TGF-β) superfamily members and the phosphorylation of Smad3; consistently, in vitro experiments also verified the above results. Our findings revealed the cardioprotective role of FST in attenuating diabetic cardiomyopathy through its anti-fibrotic effects through the TGF-β-Smad3 pathway and provided a promising therapeutic strategy for diabetic cardiomyopathy.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8353454 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy <i>via</i> the TGF-β-Smad3 Pathway.

Wang Yinhui Y Yu Kun K Zhao Chengcheng C Zhou Ling L Cheng Jia J Wang Dao Wen DW Zhao Chunxia C

Frontiers in pharmacology 20210727

Follistatin (FST) is an endogenous protein that irreversibly inhibits TGF-β superfamily members and plays an anti-fibrotic role in other diseases. However, the role of FST in diabetic cardiomyopathy remains unclear. In this study, we investigated the effects of FST on diabetic cardiomyopathy. The expression of FST was downregulated in the hearts of db/db mice. Remarkably, overexpressing FST efficiently protected against cardiac dysfunction. In addition, overexpression of FST promoted cardiac hyp ...[more]

PMID: 34385917

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Project description:BackgroundPulmonary fibrosis is a progressive and irreversible disease for which therapeutic options are currently limited. A recent in vivo study showed that tenofovir, a nucleotide analogue reverse transcriptase inhibitor, had direct antifibrotic effects on skin and liver fibrosis. Another study in vitro revealed that NS5ATP9 inhibited the activation of human hepatic stellate cells. Because of the similarity of fibrotic diseases, we hypothesized that tenofovir alafenamide fumarate (TAF), the prodrug of tenofovir, and NS5ATP9, is related to and plays a role in the suppression of pulmonary fibrosis.MethodsWe investigated the influence of NS5ATP9 on fibrosis in vitro. Human lung fibroblasts (HFL1) were transfected with short interfering RNAs or overexpression plasmids of NS5ATP9 before stimulation by human recombinant transforming growth factor-β1. The effect of TAF was evaluated in a bleomycin-induced fibrosis murine model. Male C57BL/6 mice were treated with bleomycin on day 0 by intratracheal injection and intragastrically administered TAF or vehicle. Left lung sections were fixed for histological analysis, while homogenates of the right lung sections and HFL1 cells were analyzed by western blotting and quantitative reverse transcription polymerase chain reaction.ResultsNS5ATP9 suppressed the activation of lung fibroblasts. Upregulation of collagen type 3 (α 1 chain) and α-smooth muscle actin was observed in HFL1 cells when NS5ATP9 was silenced, and vice-versa. TAF also showed anti-fibrotic effects in mice, as demonstrated by histological analysis of fibrosis and expression of extracellular matrix components in the lung sections. Additionally, TAF inhibited transforming growth factor-β1 and phosphorylated-Smad3 synthesis in HFL1 cells and the murine model, which was accompanied by upregulation of NS5ATP9.ConclusionsOur results suggest that NS5ATP9 forms a negative feedback pathway in pulmonary fibrosis and TAF has anti-fibrotic properties as it upregulates the expression level of NS5ATP9. As TAF has been shown to be safe and well-tolerated in humans, TAF and NS5ATP9 may be useful for developing novel therapeutics for pulmonary fibrosis.

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Dataset Information

Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β-Smad3 Pathway.

Publications

Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy <i>via</i> the TGF-β-Smad3 Pathway.

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