G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS-2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography and ß-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot in heart and isolated cardiac myocytes. Sepsis increased NOS-2 expression in the heart, increased plasma NOx levels and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development and ß-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. Treatment with 1400W or in hearts taken from septic NOS2 KO mice the activation of GRK2 is reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters and prevented organ damage. Therefore, during sepsis, NOS-2-derived NO increases GRK2 that leads to a reduction in ß-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the sGC/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction.
- beta-adrenergic receptors
- G-protein receptor kinase
- inducible nitric oxide synthase
- nitric oxide
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology