Abstract 1578: Endogenous Adenosine Protects the Heart from Severe Systolic Overload Induced Ventricular Hypertrophy and Congestive Heart Failure
Adenosine regulates myocardial blood flow and protects the heart from acute ischemia-reperfusion induced damage. However, the effect of endogenous adenosine on chronic systolic overload induced left ventricular hypertrophy (LVH) and congestive heart failure (CHF) is unknown. CD73 uses AMP as substrate to generate adenosine, and CD73-deficiency attenuates extracellular adenosine production. To determine the effect of endogenous adenosine on LVH and CHF, the degree of LV hypertrophy, dilation and dysfunction in response to severe transverse aortic constriction (TAC) was determined in CD73-deficient (CD73-KO) mice and their wild type littermates. CD73-KO mice develop and grow normally without obvious cardiovascular defects or dysfunction. Although there was no difference in heart weight, lung weight, or LV function between CD73-KO mice and wild type littermates (WTL) under unstressed conditions, CD73-KO mice demonstrated more severe myocardial hypertrophy, LV dilation and LV dysfunction in response to systolic overload produced by TAC for 2 weeks or 4 weeks. Thus, after TAC of 4 weeks duration, LV ejection fraction decreased to 42.8±2.8% and 56.5±3.7% in CD73-KO mice and WTL, respectively (p<0.05). Consistent with more severe LV dilation and dysfunction, CD73-KO mice responded to TAC with a markedly greater increase of myocardial ANP and myocardial fibrosis than their wild type littermates. Furthermore, TAC for two weeks resulted in significantly greater increases of myocardial IL-6, p-Erk1, p-Erk-2, and p-mTOR in CD73-KO mice than WTL. The finding that CD73-KO exacerbates ventricular hypertrophy and dysfunction induced by systolic overload suggests a critical role of endogenous adenosine in mediating the cardiac adaptation to hemodynamic stress.