Adenosine A3 receptor deficiency exerts unanticipated protective effects on the pressure-overloaded left ventricle

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

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Background - Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A 1 receptors (A1R) and A3 receptors (A 3R) 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 A 3R 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.

Original languageEnglish (US)
Pages (from-to)1713-1721
Number of pages9
JournalCirculation
Volume118
Issue number17
DOIs
StatePublished - Oct 21 2008

Keywords

  • Adenosine
  • Free radicals
  • Heart failure
  • Hypertrophy
  • Oxidative stress

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