Pressure overload causes cardiac hypertrophy in β1- and β2-adrenergic receptor double knockout mice

Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Consiglio Nazionale delle Ricerche, Rome, Italy.
Journal of Hypertension (Impact Factor: 4.72). 04/2006; 24(3):563-71. DOI: 10.1097/01.hjh.0000203843.41937.2a
Source: PubMed


Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time.
Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and beta-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DbetaKO banded mice, and were significantly greater than in sham controls.
Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.

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    • "There has been no study to examine, utilizing the b-adrenoceptor KO strains, the development of pressureoverload hypertrophy, except a recent one on the b 1/2 -KO model (Palazzesi et al., 2006). In that study, no phenotypic difference between b 1/2 -KO and littermate controls was identified either at baseline or following a 4-week period of TAC (Palazzesi et al., 2006). Considering the mixed background of the b 1/2 -KO strain used in the present study (C57B6/129sv/DBA/FVB) (Rohrer et al., 1999), we also tested another three relevant strains of WT mice by inducing TAC. "
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    ABSTRACT: The role of beta-adrenoceptors in heart disease remains controversial. Although beta-blockers ameliorate the progression of heart disease, the mechanism remains undefined. We investigated the effect of beta-adrenoceptors on cardiac hypertrophic growth using beta(1)- and beta(2)-adrenoreceptor knockout and wild-type (WT) mice. Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiography and micromanometry. At 4 and 12 weeks after aortic banding, the left ventricle:body mass ratio was increased by 80-87% in wild-type mice, but only by 15% in knockouts, relative to sham-operated groups. Despite the blunted hypertrophic growth, ventricular function in knockouts was maintained. WT mice responded to pressure overload with up-regulation of gene expression of inflammatory cytokines and fibrogenic growth factors, and with severe cardiac fibrosis. All these effects were absent in the knockout animals. Our findings of a markedly attenuated cardiac hypertrophy and fibrosis following pressure overload in this knockout model emphasize that beta-adrenoceptor signalling plays a central role in cardiac hypertrophy and maladaptation following pressure overload.
    British Journal of Pharmacology 03/2008; 153(4):684-92. DOI:10.1038/sj.bjp.0707622 · 4.84 Impact Factor
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    • "The findings by Patrizio et al. (2007) would have been strengthened by providing measures of cardiomyocyte hypertrophy (such as cell size, protein synthesis), exploring potential signalling mechanisms and validating the results from pharmacological approaches by using genetically engineered models, such as b-adrenoceptor knockout mice. Actually, a recent paper from the same group found no difference between the b 1 -and b 2 -adrenoceptor dualknockout and wild-type mice in the extent of TACinduced hypertrophy, fetal gene expression and fibrosis (Palazzesi et al., 2006), findings contradictory to the current report (Patrizio et al., 2007). Furthermore, although hypertrophy was inhibited, b-blockade had no effect on the suppressed SERCA expression (Patrizio et al., 2007). "
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    ABSTRACT: While the expression patterns of cardiac hypertrophy-related genes have been well documented and widely used as markers for hypertrophy, recent research has revealed uncoupling of hypertrophy-related gene profiles and hypertrophic growth. The role of β-adrenergic signalling in the development of hypertrophy is incompletely understood. The finding of an upregulated expression of hypertrophy-related genes but a suppressed hypertrophy following β-blockade reveals previously unrecognized sympatho-adrenergic mechanisms of hypertrophic growth. British Journal of Pharmacology (2007) 152, 169–171; doi:10.1038/sj.bjp.0707353
    British Journal of Pharmacology 10/2007; 152(2):169-71. DOI:10.1038/sj.bjp.0707353 · 4.84 Impact Factor
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    ABSTRACT: Calcineurin and its downstream effectors nuclear factor of activated T-cells 3 (NFAT3) and zinc finger-containing transcription factor (GATA4) have been implicated in the development of cardiac hypertrophy. The aims of the present study were to investigate alterations in the calcineurin/NFAT3/GATA4 pathway in pressure-overload hypertrophy, and to determine whether adrenergic receptor blockade affects this signaling pathway. In aorta-banded rats compared with sham-operated rats, a significant increase in the phosphorylation levels of calcineurin and GATA4 was observed (both p<0.05), while the NFAT3 phosphorylation level was markedly decreased (p<0.05). Oral administration of either the non-selective β blocker/α-1 blocker carvedilol or the selective β-1 blocker metoprolol, but not the selective α-1 blocker terazosin, significantly suppressed the activated calcineurin/NFAT3/GATA4 pathway (all p<0.05) in addition to inducing a regression of cardiac hypertrophy. Pressure overload-induced up-regulation of c-myc was markedly attenuated by treatment with either carvedilol or metoprolol (both p<0.05). The present findings may expand our understanding of the correlation between sympathetic activity and the calcineurin/NFAT3/GATA4 pathway, and highlight these signal transducers as effective targets in the management of pressure overload-induced cardiac hypertrophy.
    Molecular Medicine Reports 05/2010; 3(3):497-501. DOI:10.3892/mmr_00000287 · 1.55 Impact Factor
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