Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade.

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Physiology

Background:

• Endothelin-1 (ET-1) plays a role in cardiovascular homeostasis.
• The precise impact of ET-1 dysregulation on cardiac structure and function requires further elucidation.

Purpose of the Study:

• To investigate the functional consequences of varying endothelin-1 gene expression levels on cardiac phenotype.
• To explore therapeutic strategies targeting oxidative stress and matrix metalloproteinase activity in ET-1-related cardiac dysfunction.

Main Methods:

• Generation of mouse models with distinct endothelin-1 gene expression levels (L/L, L/+, +/+, H/+).
• Utilized Cre-loxP recombination for spatiotemporal switching of gene expression.
• Pharmacological interventions with an epithelial sodium channel antagonist and a superoxide dismutase mimetic.
• Genetic manipulation via knockout of matrix metalloproteinase 9 (Mmp9).

Main Results:

• Low endothelin-1 expression (L/L, L/+) induced dilated cardiomyopathy, hypertension, increased plasma volume, elevated ventricular superoxide, and increased Mmp9 expression.
• High endothelin-1 expression (H/+) led to decreased plasma volume and stiff hearts.
• Switching expression from low to high ET-1 normalized cardiac abnormalities.
• Superoxide dismutase mimetic and Mmp9 absence partially improved cardiac function, highlighting the roles of oxidative stress and Mmp9.

Conclusions:

• Endothelin-1 is crucial for normal cardiac contractile function, regulation of superoxide and Mmp9, and myocardial collagen content.
• Even a moderate reduction in endothelin-1 gene expression significantly impairs cardiac function.
• Targeting superoxide and Mmp9 presents potential therapeutic avenues for ET-1-associated cardiovascular diseases.