C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness.
JCI Insight
; 5(22)2020 11 19.
Article
in En
| MEDLINE
| ID: mdl-33055420
ABSTRACT
Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, modulates titin-based ventricular compliance. To dissect GC-B-mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte-restricted GC-B deletion (CM GC-B-KO mice). The impact on heart morphology and function, myocyte passive tension, and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC). Pressure overload increased left ventricular endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B-KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B-deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure overload.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinases
/
Receptors, Atrial Natriuretic Factor
/
Natriuretic Peptide, C-Type
/
Myocytes, Cardiac
/
Heart Failure
/
Myocardium
Type of study:
Etiology_studies
Limits:
Animals
Language:
En
Journal:
JCI Insight
Year:
2020
Document type:
Article
Affiliation country:
Germany