Adenosine Inhibits Lipopolysaccharide-Induced Cardiac Expression of Tumor Necrosis Factor-α

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Abstract
—Tumor necrosis factor-α (TNF-α) is elevated in the failing heart. Very little is known about regulation of TNF-α in cardiomyocytes. TNF-α expression by macrophages is diminished by adenosine. Therefore, we hypothesized that a similar mechanism might occur in the heart. Neonatal rat myocytes were stimulated with lipopolysaccharide (LPS), and TNF-α was measured by ELISA. In the absence of LPS, myocytes did not release TNF-α in the medium. After exposure to LPS, TNF-α increased to 70.1±3.5 pg/mL at 6 hours. Immunofluorescent staining confirmed that TNF-α was expressed in myocytes. Adenosine decreased TNF-α in a dose-dependent manner (1 to 100 μmol/L, 37% to 65% decrease, P<.01). Adenosine also decreased TNF-α in cell homogenates by 78% (P<.0001). The effect of adenosine could be replicated by the A2 agonist PD-125944 (DPMA), by cAMP agonists 8-bromo-cAMP, forskolin, and Ro 20–1724, but not by A1 and A3 agonists. Conversely, the effect of adenosine could be suppressed by the adenylate cyclase inhibitor MDL-12,330. Adenosine also inhibited TNF-α in adult rat ventricular myocytes (−60%, P<.005) and rat papillary muscles (−55%, P<.05). In neonatal myocytes, adenosine normalized LPS-induced calcium changes and improved LPS-induced negative inotropic (P<.01) and negative lusitropic (P<.01) effects. Our results demonstrate that adenosine can significantly diminish TNF-α levels in the heart. The effect appears to be mediated by the A2 receptor and transduced through a G protein–adenylyl cyclase pathway. These results may explain some cardioprotective effects of adenosine and provide a novel pharmacological intervention in congestive heart failure.

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