Adenosine A3 receptor deficiency exerts unanticipated protective effects on the pressure-overloaded left ventricle.
BACKGROUND
Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A(1) receptors (A(1)R) and A(3) receptors (A(3)R) is not known.


RESULTS
To test the hypothesis that A(1)R and A(3)R can protect the heart against systolic overload, we exposed A(3)R gene-deficient (A(3)R knockout [KO]) mice and A(1)R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A(3)R KO attenuated 5-week TAC-induced left ventricular hypertrophy (ratio of ventricular mass/body weight increased to 7.6+/-0.3 mg/g in wild-type mice compared with 6.3+/-0.4 mg/g in KO mice), fibrosis, and dysfunction (left ventricular ejection fraction decreased to 43+/-2.5% and 55+/-4.2% in wild-type and KO mice, respectively). A(3)R KO also attenuated the TAC-induced increases of myocardial atrial natriuretic peptide and the oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal. In contrast, A(1)R KO increased TAC-induced mortality but did not alter ventricular hypertrophy or dysfunction compared with wild-type mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction and increased myocardial 3'-nitrotyrosine. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine reduced cell area, protein synthesis, atrial natriuretic peptide, and 3'-nitrotyrosine. Antagonism of A(3)R significantly potentiated the antihypertrophic effects of 2-chloroadenosine.


CONCLUSIONS
Adenosine exerts protective effects on the overloaded heart, but the A(3)R acts counter to the protective effect of adenosine. The data suggest that selective attenuation of A(3)R activity might be a novel approach to treat pressure overload-induced left ventricular hypertrophy and dysfunction.
Center for Vascular Biology, University of Minnesota, Minneapolis, MN 55455, USA.
Zhongbing
Z
Lu
John
J
Fassett
Xin
X
Xu
Xinli
X
Hu
Guangshuo
G
Zhu
Joel
J
French
Ping
P
Zhang
Jurgen
J
Schnermann
Robert J
RJ
Bache
Yingjie
Y
Chen
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043684:Receptor, Adenosine A3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology; D017725:Ventricular Pressure / Q000235:genetics / Q000502:physiology*
D043684:Receptor, Adenosine A3