Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice.

Abstract

OBJECTIVE:

To investigate how permanent inhibition of guanylyl cyclase A receptor (GC-A) affects cardiac function.

METHODS:

Hearts of GC-A-/- and corresponding wild type mice (GC-A+/+) were characterised by histological, western blotting, and northern blotting analyses. Cardiac function was evaluated in isolated, working heart preparations.

RESULTS:

At 4 months of age, GC-A-/- mice had global cardiac hypertrophy (about a 40% increase in cardiac weight) without interstitial fibrosis. Examination of heart function found a significant delay in the time of relaxation; all other parameters of cardiac contractility were similar to those in wild type mice. At 12 months, the hypertrophic changes were much more severe (about a 61% increase in cardiac weight), together with a shift in cardiac gene expression (enhanced concentrations of atrial natriuretic peptide (3.8-fold), B type natriuretic peptide (2-fold), beta myosin heavy chain (1.6-fold) and alpha skeletal actin (1.7-fold) mRNA), increased expression of cytoskeletal tubulin and desmin (by 29.6% and 25.6%, respectively), and pronounced interstitial fibrosis. These changes were associated with significantly impaired cardiac contractility (+dP/dt decreased by about 10%) and relaxation (-dP/dt decreased by 21%), as well as depressed contractile responses to pressure load (all p < 0.05).

CONCLUSIONS:

Chronic hypertension in GC-A-/- mice is associated with progressive cardiac changes--namely, initially compensated cardiomyocyte hypertrophy, which is complicated by interstitial fibrosis and impaired cardiac contractility at later stages.

• Authors: M Kuhn, R Holtwick, H A Baba, J C Perriard, W Schmitz, E Ehler
• Journal: Heart (British Cardiac Society) (Heart) Vol. 87 Issue 4 Pg. 368-74 (Apr 2002) ISSN: 1468-201X [Electronic] England
• PMID: 11907014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cell Surface
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Blood Pressure (physiology)
• Blotting, Northern
• Blotting, Western
• Cardiomegaly (etiology, pathology, physiopathology)
• Endomyocardial Fibrosis (etiology)
• Guanylate Cyclase
• Hypertension (etiology)
• Immunohistochemistry
• Male
• Mice
• Receptors, Atrial Natriuretic Factor
• Receptors, Cell Surface (deficiency)
• Ventricular Function, Left (physiology)