Abstract 3396: Controlled Over-expression of A2A -R Provides Protection From Pressure Induced Cardiac Failure Through Down Regulation of GATA-4
Background: Adenosine binds to G protein-coupled receptors (R) located on the cardiomyocyte (A1-R, A2A-R and A3-R). Using a cardiac-specific and inducible promoter, we selectively over-expressed A2A-R in FVB mice. These mice were phenotypically normal but demonstrated a marked increase in cardiac contractility and significantly higher systolic but not diastolic [Ca2+]i, higher maximal contraction amplitudes, maximal shortening and relengthening velocities, and a significantly enhanced sarcoplasmic reticulum Ca2+ uptake activity (p<0.01). In the present study, we tested the hypothesis that cardiac A2A-R may be protective against pressure-induced heart failure secondary to transverse aortic constriction (TAC).
Methods and Results: We compared the effect of aortic constriction in mice over expressing A2A-R (N=10) as compared to wild type mice (WT) (N=17). Echocardiograms were obtained at baseline, 2, 4, 8, 12,14Wks and hearts were harvested at 14wks. A2A -R mice had preserved cardiac function and showed tolerance to TAC induced pressure overload when compared to WT at 14 wks. WT mice developed a significant decrease in cardiac function, and increase in end systolic and diastolic dimensions and a higher heart weight to body weight ratio (HW/BW) (P<0.001). Pressure overload induced hypertrophy and failure is associated with marked alterations in cardiac gene expression; induction of β-myosin heavy chain (β-MHC), and atrial natriuretic factor (ANF). These changes are mediated by activation of GATA-4. Therefore, we examined expression levels of GATA-4, β-MHC, and ANP after TAC in A2A -R and WT mice. GATA-4 (P<0.005), ANP (P<0.05) and β-MHC (P<0.03) were significantly higher in WT mice after TAC than in mice over-expressing A2A -AR. Indeed, βMHC expression increased by 70% after TAC in WT mice vs. 7% in A2A-R mice.
Conclusion: A2A -R over-expression is protective against pressure induced heart failure secondary to TAC. This cardioprotective effect appears to be secondary to A2A inhibition of GATA-4 expression.