Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Fibrosis Research

Background:

• Endothelin-1 (ET-1) is a vasoconstrictor implicated in cardiovascular diseases.
• Connective tissue growth factor (CTGF) is a fibrotic mediator found in atherosclerotic lesions, myocardial infarction, and hypertension.
• CTGF influences cell proliferation, apoptosis, migration, ECM accumulation, and plays roles in tissue repair and fibrosis.

Purpose of the Study:

• To investigate the signaling pathways through which ET-1 triggers CTGF expression in cardiomyocytes.
• To determine the role of CTGF in ET-1-induced extracellular matrix accumulation.

Main Methods:

• Utilized HL-1 cells as a model system for adult mouse atrial-muscle cells.
• Analyzed CTGF promoter activation and expression at mRNA and protein levels.
• Performed real-time PCR on rat heart preparations perfused with ET-1.
• Investigated intracellular signaling pathways including ERK, c-fos, c-jun (via ChIP analysis), and EGFR.
• Employed CTGF silencing to assess its role in ET-1 induced ECM accumulation.

Main Results:

• ET-1 activated the CTGF promoter and increased CTGF expression in HL-1 cells.
• CTGF induction by ET-1 was confirmed in isolated rat heart preparations.
• ET-1 signaling involved ET receptors, EGFR, ERK activation, and AP-1 components (c-fos, c-jun).
• CTGF silencing abolished decorin expression in ET-1 treated cells, indicating CTGF's role in ECM accumulation.

Conclusions:

• CTGF acts as a mediator of ET-1's profibrotic effects in cardiomyocytes.
• CTGF is involved in ET-1 induced extracellular matrix accumulation through direct and downstream mechanisms.
• CTGF inhibitors represent a potential therapeutic strategy for ET-1-related cardiovascular diseases.