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Published on: June 3, 2018
SFRP4 Knockdown Attenuates Dsg2-Deficient Arrhythmogenic Cardiomyopathy by Down-Regulating TGF-β and Smad3
Wei Li1, Meixiang Wang1, Zhongbao Ruan2
1Department of Cardiology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, Jiangsu, China.
Insights
Secreted frizzled-related protein 4 (SFRP4) reduction alleviates cardiac fibrosis in arrhythmogenic cardiomyopathy (ACM). SFRP4 inhibition suppressed myocardial fibrosis and cardiac dysfunction by blocking the transforming growth factor beta (TGF-β) signaling pathway.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Genetics
Background:
- Secreted frizzled-related protein 4 (SFRP4) role in cardiovascular disease is established, but its specific function in arrhythmogenic cardiomyopathy (ACM) is unclear.
- ACM is characterized by myocardial fibrosis and cardiac dysfunction.
- Desmoglein 2 (Dsg2) knockout mice serve as a model for studying ACM.
Purpose of the Study:
- To investigate the role of SFRP4 in ACM pathogenesis.
- To elucidate the molecular mechanisms by which SFRP4 influences cardiac fibrosis and function in ACM.
- To evaluate the therapeutic potential of SFRP4 inhibition in ACM.
Main Methods:
- Differential gene expression analysis using Gene Expression Omnibus (GEO) data.
- Utilized a Dsg2 knockout mouse model for ACM.
- Assessed myocardial fibrosis via histological analysis and cardiac function through echocardiography.
- Investigated cardiac fibroblast (CF) migration using wound healing assays.
- Analyzed SFRP4, TGF-β signaling pathway components (TGFBR2, TGF-β2, Smad3) via qPCR and Western blot.
Main Results:
- SFRP4 was significantly upregulated in Dsg2 knockout mice, a model of ACM.
- SFRP4 knockdown ameliorated myocardial fibrosis, ventricular dilation, and improved cardiac compliance in Dsg2 knockout mice.
- SFRP4 inhibition reduced Angiotensin II-induced cardiac fibroblast migration.
- SFRP4 activates the TGF-β signaling pathway, as evidenced by increased expression of TGFBR2, TGF-β2, and Smad3, which was reversed by SFRP4 knockdown.
Conclusions:
- SFRP4 plays a critical role in promoting cardiac fibrosis and dysfunction in ACM.
- Inhibition of SFRP4 represents a potential therapeutic strategy for ACM.
- SFRP4 exerts its pro-fibrotic effects in ACM by activating the TGF-β signaling pathway.
Abstract:
Although secreted frizzled-related protein 4 (SFRP4) has been linked to the development of cardiovascular diseases; it is yet unknown how exactly it functions in arrhythmogenic cardiomyopathy (ACM) remains unclear. Data from the Gene Expression Omnibus (GEO) were used to identify genes that were differentially expressed and linked to ACM. A mouse model known as desmoglein 2 (Dsg2) knockout (Dsg2-/-) was employed to investigate ACM. Myocardial fibrosis was evaluated by histological analysis, while heart function was evaluated by echocardiography. Angiotensin II (Ang II) was used to stimulate cardiac fibroblasts (CFs) and cause a fibrotic phenotype. The ability of CFs to migrate was evaluate using a wound healing assay. Gene Set Enrichment Analysis (GSEA) was used to do an enrichment study of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The levels of SFRP4, transforming growth factor beta receptor 2 (TGFBR2), TGF-β2, and Smad family member 3 (Smad3) were assessed using quantitative real-time PCR and Western blot. Our findings show that SFRP4 is highly expressed in Dsg2-/- mice. SFRP4 knockdown markedly reduced myocardial fibrosis, ventricular compliance, and cardiac dilation in Dsg2-/- mice. The level of SFRP4 was higher in CFs treated with Ang II, andSFRP4 inhibition markedly decreased the migration of Ang II-induced CFs. Moreover, SFRP4 activates the TGF-β signaling pathway, with SFRP4 knockdown resulting in a significant decrease in the expression levels of TGF-β2, TGFBR2, and Smad3 in Dsg2-/- mice. In summary, SFRP4 knockdown reduced cardiac fibrosis in ACM by inhibiting the TGF-β signaling pathway.
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