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Knockout of β 1 ‐ and β 2 ‐adrenoceptors attenuates pressure overload‐induced cardiac hypertrophy and fibrosis
Author(s) -
Kiriazis H,
Wang K,
Xu Q,
Gao XM,
Ming Z,
Su Y,
Moore XL,
Lambert G,
Gibbs M E,
Dart A M,
Du XJ
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707622
Subject(s) - pressure overload , muscle hypertrophy , medicine , fibrosis , knockout mouse , gene knockout , endocrinology , ventricle , cardiac fibrosis , cardiac function curve , heart failure , cardiac hypertrophy , biology , receptor , gene , biochemistry
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. British Journal of Pharmacology (2008) 153 , 684–692; doi: 10.1038/sj.bjp.0707622 ; published online 14 January 2008