Abstract 306: Proinflammatory Prostaglandin E Impairs Adrenergic Contractility in Animal Hearts

Abstract

Introduction: Inflammation is a major risk factor for heart failure; inflammatory prostaglandin E is elevated in myocardium, and has been associated with development of heart failure via cardiac LV remodeling, but the mechanisms remain unclear. Hypothesis: We hypothesize that proinflammatory prostaglandin signaling might affect Left ventricular contractility by directly impairing β-adrenergic (βAR) signaling. Methods and Results: Pretreatment with Prostaglandin E impairs intracellular PKA phosphorylation of substrates in myocardium and cardiac contractile responses under β-adrenergic stimulation. Both prostaglandin E and β-adrenergic agonist isoproterenol induce intracellular cAMP activities in myocytes. However, the cAMP signal under prostaglandin stimulation is confined along the plasma membrane whereas the cAMP signal under isoproterenol stimulation is distributed throughout the cells, including the intracellular sarcoplasmic reticulum (SR), a calcium storage compartment critical for myocyte calcium signaling and contractile response. Interestingly, the prostaglandin E-induced cAMP signal is sufficient for PKA activation, leading phosphorylation and activation of phosphodiesterase 4 on the plasma membrane, a group of enzymes associated with membrane βARs for cAMP degradation. Moreover, pretreatment of prostaglandin E prevents dissociation of phosphodiesterase 4 from βAR induced by isoproterenol, a step necessary for cAMP diffusion from the plasma membrane to the intracellular SR. Together, prostaglandin E induces activation of phosphodiesterase 4 in βAR complex and prevents the cAMP diffusion from the plasma membrane to the SR under isoproterenol stimulation, and inhibits calcium signaling and contractile response in myocytes and animal hearts. Conclusions: This study provides a novel mechanism underlying the phosphodiesterase-mediated signaling crosstalk between two neurohormonal stimulation in myocardium under chronic conditions, and suggests that proinflammatory prostaglandin signaling may impair β-adrenergic contractile in the development of heart failure.