Knockout of beta1- and beta2-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis

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.