n(6)-cyclopentyladenosine and Aortic-Valve-Stenosis

Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of cardiac hypertrophy, while the activation of adenosine receptors has been shown to exert antihypertrophic effect on the heart. However, it remains unknown whether adenosine can attenuate hypertrophy induced by TNF-α. This study was aimed to address this issue using transverse aortic constriction (TAC) mouse models and cultured neonatal rat cardiomyocytes. Plasma TNF-α was significantly increased in hypertrophied hearts (Sham vs TAC group: 46.8±2.5 vs 67.0±1.6pg/ml, P=0.021), while myocardial TNF-α level, expression of TNF receptor 1 and TNF-α-converting enzyme were positively correlated with heart weight to body weight ratio (r=0.930, 0.676 and 0.891, respectively, P<0.01-0.05). Myocardial adenosine levels were increased significantly at 4 weeks (Sham vs TAC group: 16.15±1.59 vs 86.54±13.49 nmol/mg protein, P<0.01) and decreased from 6 to 11 weeks after TAC. N6-cyclopentyladenosine, an adenosine A1 receptor agonist inhibited protein synthesis of cardiomyocytes induced by TNF-α in a dose-dependent manner. This antihypertrophic effect could not be mimicked by agonists of A2a, A2b and A3 adenosine receptors. These findings indicate that TNF-α signal system plays important role in the process of cardiac hypertrophy, and activation of adenosine receptor 1 inhibits hypertrophy of cardiomyocytes induced by TNF-α.

Topics: ADAM Proteins; ADAM17 Protein; Adenosine; Adenosine A1 Receptor Agonists; Animals; Animals, Newborn; Aorta; Aortic Valve Stenosis; Cardiomyopathy, Hypertrophic; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Ligation; Lung; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Organ Size; Rats; Receptor, Adenosine A1; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Tumor Necrosis Factor-alpha