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(Circulation. 2008;118:1713-1721.)
© 2008 American Heart Association, Inc.

Heart Failure

Adenosine A₃ Receptor Deficiency Exerts Unanticipated Protective Effects on the Pressure-Overloaded Left Ventricle

Zhongbing Lu, PhD^*; John Fassett, PhD^*; Xin Xu, PhD^*; Xinli Hu, PhD; Guangshuo Zhu, MD; Joel French, PhD; Ping Zhang, PhD; Jurgen Schnermann, PhD; Robert J. Bache, MD; Yingjie Chen, MD, PhD

From the Center for Vascular Biology (Z.L., X.X., X.H., G.Z., Y.C.) and Cardiovascular Division, Department of Medicine (J. Fassett, X.H., G.Z., J. French, P.Z., R.J.B., Y.C.), University of Minnesota, Minneapolis; and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md (J.S.).

Correspondence to Yingjie Chen, MD, PhD, University of Minnesota, Mayo Mail Cod 508, 420 Delaware St SE, Minneapolis, MN 55455. E-mail chenx106{at}umn.edu

Received April 24, 2008; accepted July 25, 2008.

Background— Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A₁ receptors (A₁R) and A₃ receptors (A₃R) is not known.

Methods and Results— To test the hypothesis that A₁R and A₃R can protect the heart against systolic overload, we exposed A₃R gene-deficient (A₃R knockout [KO]) mice and A₁R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A₃R 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). A₃R KO also attenuated the TAC-induced increases of myocardial atrial natriuretic peptide and the oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal. In contrast, A₁R 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 A₃R significantly potentiated the antihypertrophic effects of 2-chloroadenosine.

Conclusions— Adenosine exerts protective effects on the overloaded heart, but the A₃R acts counter to the protective effect of adenosine. The data suggest that selective attenuation of A₃R activity might be a novel approach to treat pressure overload-induced left ventricular hypertrophy and dysfunction.

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CLINICAL PERSPECTIVE

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