Dataset Information

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

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.

SUBMITTER: Kiriazis H

PROVIDER: S-EPMC2259198 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Kiriazis H H Wang K K Xu Q Q Gao X-M XM Ming Z Z Su Y Y Moore X-L XL Lambert G G Gibbs M E ME Dart A M AM Du X-J XJ

British journal of pharmacology 20080114 4

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiogr ...[more]

PMID: 18193078

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Project description:Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload-induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and ?-myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

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

Similar Datasets

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