Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Endocrinology

Background:

• Heart failure (HF) remains a leading cause of mortality despite therapeutic advances.
• Identifying novel pathophysiological mechanisms is crucial for developing effective HF treatments.

Purpose of the Study:

• To investigate the role of corticotropin releasing hormone receptor 2 (Crhr2) in cardiac function and heart failure.
• To evaluate Crhr2 as a potential therapeutic target for heart failure.

Main Methods:

• Utilized mouse models with continuous infusion of the Crhr2 agonist urocortin 2 (Ucn2) and cardiomyocyte-specific Crhr2 deletion.
• Assessed cardiac function via left ventricular ejection fraction measurements.
• Quantified plasma Ucn2 levels in human heart failure patients and healthy controls.
• Administered a Crhr2 antagonist to mice subjected to pressure overload.

Main Results:

• Crhr2 is highly expressed in cardiomyocytes.
• Ucn2 infusion reduced left ventricular ejection fraction in mice.
• Plasma Ucn2 levels were significantly elevated in heart failure patients.
• Crhr2 deletion in cardiomyocytes protected against cardiac dysfunction.
• Crhr2 antagonist treatment prevented heart failure development and normalized cAMP signaling.

Conclusions:

• Constitutive Crhr2 activation contributes to cardiac dysfunction.
• Crhr2 blockade emerges as a promising therapeutic strategy for chronic heart failure.