A Gene Expression Profile of the Myocardial Response to Clenbuterol |
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Authors: | Enrique Lara-Pezzi Cesare M N Terracciano Gopal K R Soppa Ryszard T Smolenski Leanne E Felkin Magdi H Yacoub Paul J R Barton |
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Affiliation: | (1) Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College, Hill End Road, Harefield, Middlesex, UB9 6JH, UK |
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Abstract: | Clenbuterol is currently being used as part of a clinical trial into a novel therapeutic approach for the treatment of end-stage
heart failure. The purpose of this study was to determine the global pattern of myocardial gene expression in response to
clenbuterol and to identify novel targets and pathways involved. Rats were treated with clenbuterol (n = 6) or saline (n = 6) for periods of 1, 3, 9, or 28 days. Rats treated for 28 days were also subject to continuous electrocardiogram analysis
using implantable telemetry. RNA was extracted from rats at days 1 and 28 and used from microarray analysis, and further samples
from rats at days 1, 3, 9, and 28 were used for analysis by real-time polymerase chain reaction. Clenbuterol treatment induced
rapid development of cardiac hypertrophy with increased muscle mass at day 1 and elevated heart rate and QT interval throughout
the 28-day period. Microarray analysis revealed a marked but largely transitory change in gene expression with 1,423 genes
up-regulated and 964 genes down-regulated at day 1. Up-regulated genes revealed an unexpected association with angiogenesis
and integrin-mediated cell adhesion and signaling. Moreover, direct treatment of endothelial cells cultured in vitro resulted
in increased cell proliferation and tube formation. Our data show that clenbuterol treatment is associated with rapid cardiac
hypertrophy and identify angiogenesis and integrin signaling as novel pathways of clenbuterol action. The data have implications
both for our understanding of the physiologic hypertrophy induced by clenbuterol and for treatment of heart failure.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Clenbuterol Microarray Myocardium Hypertrophy |
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