Knockout of β1‐ and β2‐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 β₁‐ and β₂‐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. British Journal of Pharmacology (2008) 153, 684–692; doi:10.1038/sj.bjp.0707622; published online 14 January 2008