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Published on: January 18, 2019
Electrical field stimulation induces cardiac fibroblast proliferation through the calcineurin-NFAT pathway
Qing-Qing Chen1, Wei Zhang, Xiang-Fan Chen
1Department of Pharmacology, Nantong University Medical College, Nantong, P.R. China.
Abstract:
Most cardiac diseases are associated with fibrosis. Calcineurin (CaN) is regulated by Ca(2+)/calmodulin (CaM). The CaN-NFAT (nuclear factor of activated T cell) pathway is involved in the process of cardiac diseases, such as cardiac hypertrophy, but its effect on myocardial fibrosis remains unclear. The present study investigates whether the CaN-NFAT pathway is involved in cardiac fibroblast (CF) proliferation induced by electrical field stimulation (EFS), which recently became a popular treatment for heart failure and cardiac tissue engineering. CF proliferation was evaluated by a cell survival assay (MTT) and cell counts. Myocardial fibrosis was assessed by collagen I and collagen III protein expression. Green fluorescent protein (GFP)-tagged NFAT was used to detect NFAT nuclear translocation. CF proliferation, myocardial fibrosis, CaN activity, and NFAT nuclear translocation were enhanced by EFS. More importantly, these effects were abolished by CaN inhibitors, dominant negative CaN (DN-CaN), and CaN gene silenced with siRNA. Furthermore, buffering intracellular Ca(2+) with BAPTA-AM and blocking Ca(2+) influx with nifedipine suppressed EFS-induced increase in intracellular Ca(2+) and CF proliferation. These results suggested that the CaN-NFAT pathway mediates CF proliferation, and that the CaN-NFAT pathway might be a possible therapeutic target for EFS-induced myocardial fibrosis and cardiac tissue engineering.
Insights
Electrical field stimulation (EFS) promotes cardiac fibroblast proliferation and fibrosis via the calcineurin-nuclear factor of activated T cell (CaN-NFAT) pathway. Inhibiting this pathway may offer therapeutic strategies for cardiac tissue engineering and heart failure.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Biomedical Engineering
Background:
- Cardiac fibrosis is a hallmark of many heart diseases.
- The calcineurin-nuclear factor of activated T cell (CaN-NFAT) pathway's role in myocardial fibrosis is not fully understood.
- Electrical field stimulation (EFS) is an emerging treatment for heart failure and cardiac tissue engineering.
Purpose of the Study:
- To investigate the involvement of the CaN-NFAT pathway in cardiac fibroblast (CF) proliferation induced by EFS.
- To assess the impact of EFS on myocardial fibrosis.
- To determine if the CaN-NFAT pathway is a potential therapeutic target for EFS-related cardiac conditions.
Main Methods:
- Cardiac fibroblast proliferation was measured using MTT assays and cell counts.
- Myocardial fibrosis was assessed by quantifying collagen I and III protein expression.
- NFAT nuclear translocation was visualized using GFP-tagged NFAT; CaN activity was measured. EFS effects were evaluated with CaN inhibitors, siRNA-mediated gene silencing, intracellular Ca(2+) buffering (BAPTA-AM), and Ca(2+) influx blockade (nifedipine).
Main Results:
- EFS significantly enhanced CF proliferation, myocardial fibrosis, CaN activity, and NFAT nuclear translocation.
- Inhibition of CaN (using inhibitors or siRNA) abolished these EFS-induced effects.
- Intracellular Ca(2+) buffering and blockade of Ca(2+) influx suppressed EFS-induced CF proliferation.
Conclusions:
- The CaN-NFAT pathway mediates EFS-induced cardiac fibroblast proliferation and myocardial fibrosis.
- Targeting the CaN-NFAT pathway presents a potential therapeutic strategy for managing EFS-induced myocardial fibrosis.
- This pathway is relevant for applications in cardiac tissue engineering and heart failure treatment.
