Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Translational Medicine

Background:

• Myocardial endothelin-1 (ET-1) and its receptors (ET(A), ET(B)) are upregulated in heart failure.
• The precise role of ET-1 signaling in myocardial disease pathogenesis remains unclear.

Purpose of the Study:

• To investigate the functional consequences of cardiac endothelin-1 (ET-1) overexpression.
• To elucidate the role of ET-1 signaling pathways in the development of heart failure.

Main Methods:

• Generated transgenic mice with doxycycline-inducible cardiac ET-1 overexpression.
• Assessed cardiac function, mortality, and inflammatory markers post-doxycycline withdrawal.
• Utilized ET(A)/ET(B) and ET(A)-selective antagonists to evaluate therapeutic potential.

Main Results:

• Cardiac ET-1 overexpression led to increased mortality, left ventricular dysfunction, and dilatation.
• Observed significant myocardial inflammation, including macrophage and T lymphocyte infiltration.
• Inflammatory cytokine expression (TNF-α, IFN-γ, IL-1, IL-6) and NF-κB activation were elevated.
• Combined ET(A)/ET(B) receptor blockade prolonged survival, while ET(A)-selective blockade did not.

Conclusions:

• Cardiac ET-1 overexpression is sufficient to induce inflammatory cardiomyopathy and heart failure.
• ET-1 signaling, particularly via the ET(B) receptor, plays a critical role in this inflammatory process.
• Targeting ET-1 receptors may offer a therapeutic strategy for ET-1-mediated heart failure.