Published Online
on April 7, 2008

A more recent version of this article appeared on June 1, 2008

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Submitted on January 22, 2008
Revised on February 7, 2008

Ecto-5'-Nucleotidase Deficiency Exacerbates Pressure-Overload–Induced Left Ventricular Hypertrophy and Dysfunction

Xin Xu; John Fassett; Xinli Hu; Guangshuo Zhu; Zhongbing Lu; Yunfang Li; Jurgen Schnermann; Robert J. Bache; and Yingjie Chen^*

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

^* To whom correspondence should be addressed. E-mail: chenx106{at}tc.umn.edu.

Abstract—This study examined whether endogenous extracellular adenosine acts to facilitate the adaptive response of the heart to chronic systolic overload. To examine whether endogenous extracellular adenosine can protect the heart against pressure-overload–induced heart failure, transverse aortic constriction was performed on mice deficient in extracellular adenosine production as the result of genetic deletion of CD73. Although there was no difference in left ventricular size or function between CD73-deficient mice (knockout [KO] mice) and wild-type mice under unstressed conditions, aortic constriction for 2 or 4 weeks induced significantly more myocardial hypertrophy, left ventricular dilation, and left ventricular dysfunction in KO mice compared with wild-type mice. Thus, after 2 weeks of transverse aortic constriction, left ventricular fractional shortening decreased to 27.4±2.5% and 21.9±1.7% in wild-type and KO mice, respectively (P<0.05). Consistent with a role of adenosine in reducing tissue remodeling, KO mice displayed increased myocardial fibrosis and myocyte hypertrophy compared with wild-type mice. Furthermore, adenosine treatment reduced phenylephrine-induced cardiac myocyte hypertrophy and collagen production in cultured neonatal rat cardiac myocytes and cardiac fibroblasts, respectively. Consistent with a role for adenosine in modulating cardiomyocyte hypertrophy, KO mice demonstrated increased activation of mammalian target of rapamycin signaling, accompanied by higher expression of the hypertrophy marker atrial natriuretic peptide. Conversely, the adenosine analogue 2-chloro-adenosine significantly reduced cell size, mammalian target of rapamycin/p70 ribosomal S6 kinase activation, and atrial natriuretic peptide expression in cultured neonatal cardiomyocytes. These data demonstrate that CD73 helps to preserve cardiac function during chronic systolic overload by preventing maladaptive tissue remodeling.

Key words: hypertrophy • heart failure • fibrosis • 5'-nucleotidase • adenosine

Related Article:

Extracellular Adenosine Attenuates Left Ventricular Hypertrophy Through Its Impact on the Protein Kinase and Phosphatase Interaction

Rainer Schulz and Gerd Heusch
Hypertension 2008 51: 1474-1475. [Extract] [Full Text] [PDF]

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