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Published on: June 3, 2018
Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis
Dongtak Jeong1, Min-Ah Lee2, Yan Li2
1Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
Insights
The matricellular CCN5 protein reverses cardiac fibrosis (CF) by reducing myofibroblast proliferation and promoting their apoptosis. This suggests CCN5 as a potential therapeutic target for heart failure (HF).
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Fibrosis Research
Background:
- Cardiac fibrosis (CF) increases ventricular stiffness and diastolic dysfunction, predicting poor outcomes in heart failure (HF).
- The matricellular CCN5 protein was previously identified as cardioprotective by inhibiting CF and preserving cardiac contractility.
Purpose of the Study:
- To investigate the role of CCN5 in human heart failure.
- To determine if CCN5 can reverse established cardiac fibrosis in a pressure-induced HF experimental model.
Main Methods:
- Human hearts from end-stage HF patients were analyzed.
- Transverse aortic constriction induced CF in a rodent model, followed by adeno-associated virus-mediated CCN5 gene transfer.
- Cellular and molecular changes were assessed 8 weeks post-gene transfer.
Main Results:
- CCN5 expression was significantly reduced in failing human hearts.
- CCN5 gene transfer reversed established CF, reducing myofibroblast content.
- CCN5 inhibited TGF-β signaling, endothelial-mesenchymal transition, and fibroblast-to-myofibroblast differentiation, while inducing myofibroblast apoptosis via the intrinsic pathway.
Conclusions:
- CCN5 effectively reverses established cardiac fibrosis by inhibiting myofibroblast generation and promoting their apoptosis.
- CCN5 presents a novel therapeutic strategy for developing targeted anti-fibrotic therapies for heart conditions.
Background:
Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility.
Objectives:
This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload.
Methods:
Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined.
Results:
Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule.
Conclusions:
CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.
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