Dj. Sheridan et al., beta(2)-adrenergic receptor overexpression driven by alpha-MHC promoter isdownregulated in hypertrophied and failing myocardium, CARDIO RES, 47(1), 2000, pp. 133-141
Citations number
32
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Objective: The a-myosin heavy chain (alpha-MHC) promoter is frequently used
to direct cardiac specific transgene expression. We studied whether transg
ene expression controlled by this promoter was altered under conditions of
cardiac hypertrophy and failure. Methods: Transgenic (TG) mice overexpressi
ng human beta(2)-adrenergic receptors (P,AR) and wild type (WT) controls we
re subjected to thoracic aortic constriction (TAC) or sham operation and st
udied at I, 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 PAR activation. TAC at 1, 3 and 8 weeks produ
ced progressive LV hypertrophy which was similar between WT and TG mice. Ev
idence 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 atri
al thrombus (P<0.05 in each case). In hypertrophied TG hearts, endogenous a
lpha-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 TAG. Transgene expression, measured as human beta(2)AR mRNA, was red
uced by 45% at 1 and 3 weeks and by 70% at 8 weeks after TAG. beta(2)AR bin
ding sites were reduced by 35, 47 and 65%, respectively, at 1, 3 and 8 week
s. Conclusion: Cardiac hypertrophy and failure cause downregulation of the
endogenous alpha-MHC as well as cardiac specific overexpression of the tran
sgene directed by an alpha-MHC promoter. (C) 2000 Elsevier Science B.V. All
rights reserved.