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. 2002 Apr;87(4):368-74.
doi: 10.1136/heart.87.4.368.

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

M Kuhn  1 , R Holtwick, H A Baba, J C Perriard, W Schmitz, E Ehler
Affiliations

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

M Kuhn et al. Heart. 2002 Apr.

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.

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Figures

Figure 1
Figure 1
Confocal micrographs taken from guanylyl cyclase A receptor (GC-A) +/+ (A, C, E, G) and GC-A−/− hearts (B, D, F, H) at 4 months (A, B, E, F) and 12 months (C, D, G, H) of age (n = 4). Sections A to D were double stained with antibodies to laminin (green, to visualise the cell borders) and myomesin (red, to show cross striations in the cardiomyocytes). Sections E to H were stained with an antibody to non-muscle myosin heavy chain IIB (green, to visualise cardiac fibroblasts). A progressive increase in cardiomyocyte width can be observed in the GC-A−/− hearts (compare arrows in B and D). This was accompanied by an increased number of fibroblasts at 12 months of age (H). Bars represent 10 μm (A to D) and 20 μm (E to H).
Figure 2
Figure 2
Analysis of cytoskeletal proteins by immunohistochemistry (A) and western blotting (B). (A) Confocal micrographs of left ventricles from 12 month old GC-A+/+ (a, c) and GC-A−/− mice (b, d). Sections were double stained with antibodies to desmin (a, b) and tubulin (c, d). For desmin, similar striations at the Z disks can be observed in the GC-A+/+ and −/− hearts, but the signal is increased at the intercalated disks of GC-A−/− hearts (arrows). For tubulin, a general upregulation of signal was observed in the GC-A−/− hearts. (B) Western blotting showing increased expression of desmin and tubulin in GC-A−/− ventricles compared with GC-A+/+ (n = 5). *p < 0.05. Bars represent 20 μm.
Figure 3
Figure 3
Cardiac fibrosis in hearts of 4 and 12 month old GC-A−/− mice was estimated by histology using picrosirius red staining (A) and by northern blot analysis of α1(I) procollagen mRNA expression (B). (A) Representative sections showing focal fibrosis in hypertrophied left ventricles obtained from 12 month old GC-A−/− mice; these changes were not observed in 4 month old GC-A−/− mice or in age matched wild type (GC-A+/+) controls (n = 5). Bars represent 50 μm. (B) The α1(I) procollagen transcripts were normalised to the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (n = 12). *p < 0.05.
Figure 4
Figure 4
(A) Representative northern blot analyses showing the expression of atrial (ANP) and B type natriuretic peptide (BNP), α skeletal actin, β (β-MHC) and α myosin heavy chain, and (for reference) calsequestrin (CSQ) and GAPDH in the hearts of 12 month old GC-A+/+ and −/− mice. (B) GC-A−/− hearts show increased mRNA expression of ANP, BNP, α skeletal actin (α-sk), and β-MHC. The transcripts were normalised to the expression of CSQ, as cardiomyocyte specific gene, and compared with the expression level in GC-A+/+ mice (n = 12). *p < 0.05.
Figure 5
Figure 5
Isolated working heart preparations showing the effect of pressure loading on the contractile function of GC-A+/+ and −/− hearts obtained from (A) 4 month old (n = 5) and (B) 12 month old mice (n = 8). Hearts were perfused at 5 ml/min (preload). Aortic pressure (afterload) was sequentially adjusted by changing the height of the afterload fluid column. Left ventricular function is plotted as afterload (mm Hg) versus the rate of contraction (+dP/dt in mm Hg/s, top) and the rate of relaxation (−dP/dt in mm Hg/s, bottom). *p < 0.05 v GC-A+/+.
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