The Role of Regulator of G Protein Signaling 2 in Inflammatory Cytokine Release in Endotoxemia in Mice
Abstract
In sepsis, lipopolysaccharide (LPS) activates toll-like receptor 4 to stimulate the release of inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNF-α), leading to cardiac dysfunction. Regulator of G protein signaling 2 (RGS2) limits G protein-coupled receptor signaling by increasing the rate of G protein deactivation or inhibiting G protein-effector interactions. We hypothesized that RGS2 deficiency would enhance proinflammatory responses in endotoxemia. Adult wild-type and RGS2-/- C57BL/6 mice and neonatal cardiomyocytes were treated with LPS and assessed for inflammatory responses and cardiac function. Myocardial TNF-α expression was higher in RGS2-/- mice during endotoxemia. Additionally, cardiac function was impaired in RGS2-/- mice. Phosphorylated p38 levels were higher in the RGS2-/- myocardium in endotoxemia. In vitro, TNF-expression was higher in RGS2-/- cardiomyocytes after LPS stimulation. Our study suggests that RGS2 is cardioprotective and inhibits proinflammatory signaling via p38 in sepsis. Thus, this study suggests a novel therapeutic target for the clinical treatment of sepsis.