C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cardiac Physiology

Background:

• Heart failure is linked to titin-dependent myocardial stiffness.
• Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) enhances cardiomyocyte distensibility.
• Upstream pathways regulating PKGI-mediated titin phosphorylation remain unclear.

Purpose of the Study:

• To investigate if C-type natriuretic peptide (CNP), through guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, influences titin-based ventricular compliance.
• To elucidate the role of endogenous CNP in cardiomyocytes by generating and studying cardiomyocyte-restricted GC-B deletion (CM GC-B-KO) mice.

Main Methods:

• Generated CM GC-B-KO mice to study endogenous CNP effects.
• Assessed heart morphology, function, myocyte passive tension, and titin phosphorylation/expression.
• Utilized transverse aortic constriction (TAC) to induce pressure overload.
• Performed in vitro experiments with recombinant PKGI.

Main Results:

• Pressure overload increased cardiac CNP expression and titin phosphorylation at Ser4080.
• CM GC-B-KO mice showed abolished titin phosphorylation response and developed myocyte stiffness and cardiac dysfunction.
• TAC-induced hypertrophy and fibrosis were comparable between genotypes.
• Recombinant PKGI reversed reduced titin phosphorylation and myocyte stiffness in GC-B-deficient cardiomyocytes.

Conclusions:

• CNP signaling via GC-B/cGMP/PKGI in cardiomyocytes acts as a protective mechanism.
• This pathway prevents titin-based myocyte stiffening during the early stages of pressure overload.
• Preserving cardiomyocyte distensibility is vital for maintaining cardiac function under stress.