Knockout of β 1- and β 2-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis

Abstract

Background and purpose: The role of β-adrenoceptors in heart disease remains controversial. Although β-blockers ameliorate the progression of heart disease, the mechanism remains undefined. We investigated the effect of β-adrenoceptors on cardiac hypertrophic growth using β 1- and β 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 β-adrenoceptor signalling plays a central role in cardiac hypertrophy and maladaptation following pressure overload. © 2008 Nature Publishing Group All rights reserved.