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Comparative Study
. 2008 Feb;153(4):684-92.
doi: 10.1038/sj.bjp.0707622. Epub 2008 Jan 14.

Knockout of beta(1)- and beta(2)-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis

H Kiriazis  1 , K Wang, Q Xu, X-M Gao, Z Ming, Y Su, X-L Moore, G Lambert, M E Gibbs, A M Dart, X-J Du
Affiliations
Comparative Study

Knockout of beta(1)- and beta(2)-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis

H Kiriazis et al. Br J Pharmacol. 2008 Feb.

Abstract

Background and purpose: 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.

Experimental approach: Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiography and micromanometry.

Key results: 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.

Conclusion and implications: 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.

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Figures

Figure 1
Figure 1
Photographs of hearts at 12 weeks post-surgery (a) and gravimetric data normalized for body mass showing marked increases in normalized left ventricle (LV), right ventricle (RV) and atrial weights in wild-type (WT) mice post-aortic constriction, whereas these increases were attenuated in β1/2-knockout (KO) mice (b–d). Extent of cardiac hypertrophy in response to 2-week treatment with angiotensin-II (Ang-II) with results expressed as heart or LV mass over body mass ratio (e). *P<0.05 vs respective sham/vehicle treated group; #P<0.05 vs respective WT group; horizontal line denotes significant interaction between genotype and response to TAC.
Figure 2
Figure 2
Correlations between extent of pressure overload and left ventricular (LV) hypertrophy expressed as gravimetric LV mass normalized for body mass (LVM:BM). Plots of LVM:BM against the trans-stenotic systolic pressure gradient in mice at 4 weeks post-surgery (a). Linear regression relations reveal a significantly steeper slope for wild-type (WT) compared with β1/2-knockout (KO) mice (P<0.005). Bar graph summarizes the mean pressure gradients per group (n=4–10) (b). Plots of LVM:BM against systolic aortic pressures measured in β1/2-KO mice at 4 weeks (with avertin anaesthesia) and in WT mice at 4 and 12 weeks (with avertin or pentobarbitone/atropine anaesthesia) post-surgery (c). A blunted hypertrophic response is evident by the reduced slope of the regression line for β1/2-KO mice (P<0.001). *P<0.05 vs respective sham group.
Figure 3
Figure 3
Gene expression of atrial natriuretic peptide (ANP) (a), brain natriuretic peptide (BNP) (b), α-myosin heavy chain (α-MHC) (c), β-myosin heavy chain (β-MHC) (d), α-skeletal actin (α-SkA) (e) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) (f) in the left ventricular (LV) myocardium of wild-type (WT) and β1/2-knockout (KO) mice 12 weeks post-transverse aortic constriction (TAC). *P<0.05 vs respective sham group; #P<0.05 vs respective WT group; horizontal line denotes significant interaction between genotype and response to TAC.
Figure 4
Figure 4
Representative left ventricular (LV) sections 12 weeks post-surgery stained with Masson's trichrome showing perivascular and interstitial fibrosis (blue staining) in wild-type (WT) hearts with transverse aortic constriction (TAC) for 12 weeks (a). Bar graph (b) summarizes group data. Gene expression of transforming growth factor-β (TGF-β) (c), connective tissue growth factor (CTGF) (d) and procollagen III (e) in the LV myocardium from WT and β1/2-knockout (KO) mice 12 weeks post-TAC relative to sham-operated groups (n=6–7 per group). *P<0.05 vs respective sham group; #P<0.05 vs respective WT group; horizontal line denotes significant interaction between genotype and response to TAC. Bar=300 μm.
Figure 5
Figure 5
Interleukin-6 (IL-6) (a), IL-1β (b), monocyte chemotactic protein-1 (MCP-1) (c) and tumour necrosis factor α (TNFα) (d) gene transcripts were largely elevated in the wild-type (WT), but not in β1/2-knockout (KO) mouse left ventricles (LVs) following 12 weeks transverse aortic constriction (TAC) with respect to the sham group. *P<0.05 vs respective sham group; #P<0.05 vs respective WT group; horizontal line denotes significant interaction between genotype and response to TAC.
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