Abstract 1768: Activation of Epac1-Specific Signaling Protects Heart from Cytokine-Mediated Cardiac Dysfunction through the Inhibition of Proinflamatory Cytokine Signaling
Interaction between the sympathetic nervous system and cytokine signal remains poorly understood despite the fact that both play an important role in the development of heart failure. We have hypothesized that Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, may act as a key mediator in this interaction. The two isoforms of Epac are expressed in the heart, but their functional differences remain unknown. To examine this hypothesis, we have generated cardiac-specific Epac1 or Epac2 overexpressed transgenic mouse lines (Epac1TG, Epac2TG), and examined their responses in lipopolysaccharide (LPS)-induced cardiac dysfunction, which is known to evoke cytokine signal. At baseline, cardiac function, as evaluated by left ventricular ejection fraction (LVEF), was similar between both TG and non-transgenic (NTG). LPS (5mg/kg ip) induced similar cytokine signal as assessed by similar increases in the mRNA expression of interleukin-1β, interleukin-6, interleukin-10, or TNF-α, in both TG and NTG after injection. LPS injection instead reduced LVEF in both TG and NTG, however, the magnitude of decrease was significantly greater in NTG (44 ± 1.3%, n = 15) and Epac2TG (47 ± 2.8%, n = 6) than that in Epac1TG (55 ± 1.2%, P < 0.01, n = 15). The phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV at 6 hr after injection, an indicator of JAK-STAT pathway activation, was reduced to a greater degree in Epac1TG by 48 ± 10% (P < 0.05, n = 5) and 44 ± 7.9% (P < 0.05, n = 7), respectively, than that in NTG. In Epac2TG, STAT3 phosphorylation remain unchanged and STAT1 phosphorylation was increased by 52 ± 12% (P < 0.01, n = 11). We also examined mRNA expression of suppressor of cytokine signaling 1 (SOCS1) and 3 (SOCS3), which are known to inhibit the JAK-induced STAT phosphorylation. SOCS1 and SOCS3 were significantly increased at 6 hr after injection in both TG and NTG. However, the magnitude of SOCS1 increase was much greater (2-fold) in Epac1TG that that in NTG and Epac2TG. Putting together, these data suggest the existence of a novel cAMP/Epac1/Rap1/SOCS-1 pathway for inhibiting cytokine signaling in the heart, illustrating a new mechanism by which cyclic AMP could antagonize the development of cytokine-induced cardiac dysfunction.