Abstract 9907: Epac Activation Protects Heart From Interleukin-6-Induced Cardiac Dysfunction by Inhibiting Stat/iNOS Signaling
Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility. We hypothesized that Epac (exchange protein activated by cyclic AMP), a new target of cAMP signaling that functions independently of PKA, also plays a key role. Activation of Epac with 8-(4-chlorophenylthio)-2’-O-Me-cAMP-AM (8-CPT-AM) (10μM) for 5 hours, an Epac-selective cAMP analogue, significantly attenuated the inhibitory effect of interleukin-6 (30ng/ml) on increase of intracellular Ca2+ concentration in response to β-adrenergic stimulation with isoproterenol (ISO:10-5M) (8-CPT-AM:(-)vs.(+) 3597±306 vs. 4780±186nM, P<0.05, n=31-64 cells) and contractility as evaluated by cell shortening in response to isoproterenol (10-5M) in cardiac myocyte (8-CPT-AM:(-) vs.(+) 13.6±0.8 vs. 24.0±1.3%, P<0.01, n=24-27 cells). These effects were mediated through inhibition of STAT3 phosphorylation (8-CPT-AM:(-)vs.(+) 100±4.6 vs. 43±11.5%, P<0.01, n=6) and subsequent induction of inducible nitric oxide synthase (iNOS) protein in cardiac myocytes (8-CPT-AM(-)vs.(+) 100±10.2 vs. 42±4.0%, P<0.01, n=4). Lipopolysaccharide injection induced cytokine release and severe cardiac dysfunction in mouse. In mouse overexpressing Epac1 in the heart, however, the magnitude of such dysfunction was significantly smaller (NTG vs. TG 36±2.4 vs. 19±2.1%, P<0.01, n=15-16). Epac1 overexpression decreased phosphorylation of STAT3 (NTG vs. TG 100±11 vs. 71±6%, P<0.05, n=7) through the increased SOCS3 overexpression (NTG vs. TG 100±12.8 vs. 142±6.4, P<0.05, n=4-7) and subsequent inhibition of iNOS expression (NTG vs. TG 100±11 vs. 66+8%, n=4, P<0.05) in the heart. Activation of the cAMP/Epac pathway protected the heart against cytokine-induced cardiac dysfunction, suggesting a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac1 and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.
- © 2011 by American Heart Association, Inc.