4.8 Article

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

Journal

CIRCULATION
Volume 118, Issue 17, Pages 1713-1721

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.108.788307

Keywords

adenosine; free radicals; heart failure; hypertrophy; oxidative stress

Funding

  1. National Heart, Lung, and Blood Institute [HL71790, HL21872]
  2. National Institutes of Health
  3. American Heart Association
  4. American Heart Association Scientist Development Awards

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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. 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, 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). 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 A(3)R 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. (Circulation. 2008; 118: 1713-1721.)

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