Elevated interleukin 6(IL-6) levels in congestive heart failure are associated with myocardial damage during acute exacerbation and with chronic inflammation. Arginine vasopressin (AVP), a hormone released in response to cardiac stress, could be a factor of inflammation and fibrosis in the pathogenesis of heart failure. Recently, we have shown that AVP promotes the proliferation of neonatal rat cardiac fibroblasts (NRCFs) through a V1Avasopressin receptor-mediated G protein-coupled receptor kinase2 (GRK2) signaling. The aim of the present study is to determine the effect of AVP on IL-6 production in NRCFs and the possible involvement of the GRK2-dependent signaling in this effect. mRNA and protein levels of IL-6 were measured in NRCFs by quantitative PCR and ELISA. Cellular GRK2 activities were manipulated by including a pharmacological inhibitor or by overexpressing an inhibitory peptide, GRK2-ct. Phosphorylation and activation of nuclear factor kappa-B (NF-κB) were determined by immunoblotting and luciferase reporter gene assay. Results: (1) AVP increased the mRNA and the protein levels of IL-6 in a dose- and time-dependent manner in NRCFs; (2) Inhibition of GRK2 abolished the AVP-induced IL-6 production and NF-κB activation; (3) Pharmacological blocking of NF-κB signaling diminished the AVP-induced IL-6 production. In summary, AVP induces IL-6 production in NRCFs by activating V1A receptor signaling via a GRK2/NF-κB pathway. These findings provide a possible molecular mechanism for inflammation occurred in heart failure and other cardiac stresses.
- The American Society for Pharmacology and Experimental Therapeutics