A gene expression profile of the myocardial response to clenbuterol.
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.
Lara-Pezzi
Enrique
E
Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College, Hill End Road, Harefield, Middlesex, UB9 6JH, UK.
Terracciano
Cesare M N
CM
Soppa
Gopal K R
GK
Smolenski
Ryszard T
RT
Felkin
Leanne E
LE
Yacoub
Magdi H
MH
Barton
Paul J R
PJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002976:Clenbuterol / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015716:Electrocardiography, Ambulatory; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013686:Telemetry; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D002976:Clenbuterol