Beta(2)-adrenergic receptor overexpression driven by alpha-MHC promoter is downregulated in hypertrophied and failing myocardium.
OBJECTIVE
The alpha-myosin heavy chain (alpha-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 beta(2)-adrenergic receptors (beta(2)AR) 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 betaAR 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 alpha-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 beta(2)AR mRNA, was reduced by 45% at 1 and 3 weeks and by 70% at 8 weeks after TAC. beta(2)AR binding sites were reduced by 35, 47 and 65%, respectively, at 1, 3 and 8 weeks.


CONCLUSIONS
Cardiac hypertrophy and failure cause downregulation of the endogenous alpha-MHC as well as cardiac specific overexpression of the transgene directed by an alpha-MHC promoter.
Sheridan
D J
DJ
Baker Medical Research Institute, PO Box 6492, St. Kilda Road Central, Victoria 8008, Melbourne, Australia.
Autelitano
D J
DJ
Wang
B
B
Percy
E
E
Woodcock
E A
EA
Du
X J
XJ
D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism*; D006339:Heart Rate; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D018995:Myosin Heavy Chains / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011412:Propanolamines / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; C026777:ICI 118551; D018995:Myosin Heavy Chains