© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
β2-Adrenergic receptor overexpression driven by 
-MHC promoter is downregulated in hypertrophied and failing myocardium
Baker Medical Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia
* Corresponding author. Tel.: +613-95-224-399; fax: +613-95-211-362 xiaojun.du{at}baker.edu.au
Objective: The 
-myosin heavy chain (-MHC) promoter is frequently used to direct cardiac specific transgene expression. We studied whether transgene expression controlled by this promoter was altered under conditions of cardiac hypertrophy and failure. Methods: Transgenic (TG) mice overexpressing human β2-adrenergic receptors (β2AR) and wild type (WT) controls were subjected to thoracic aortic constriction (TAC) or sham operation and studied at 1, 3 and 8 weeks after surgery. Results: Sham operated TG mice had higher heart rates and left ventricular (LV) contractility than WT (all P<0.01), demonstrating enhanced βAR activation. TAC at 1, 3 and 8 weeks produced progressive LV hypertrophy which was similar between WT and TG mice. Evidence of heart failure was more marked in TG mice with a greater increase in weights of the right ventricle and lungs and a higher prevalence of atrial thrombus (P<0.05 in each case). In hypertrophied TG hearts, endogenous -MHC mRNA transcripts in LV were maintained at 1 and 3 weeks, but were reduced by approximately 40% relative to the sham-operated group at 8 weeks after TAC. Transgene expression, measured as human β2AR mRNA, was reduced by 45% at 1 and 3 weeks and by 70% at 8 weeks after TAC. β2AR binding sites were reduced by 35, 47 and 65%, respectively, at 1, 3 and 8 weeks. Conclusion: Cardiac hypertrophy and failure cause downregulation of the endogenous -MHC as well as cardiac specific overexpression of the transgene directed by an -MHC promoter.
KEYWORDS Gene expression; Heart failure; Hypertrophy; Receptors
1 Present address: Imperial College School of Medicine, St. Mary's Hospital, London W2 1NY, UK.
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