title: GRK2 Mediates Arginine Vasopressin-Induced Interleukin-6 Production via Nuclear Factor-κB Signaling Neonatal Rat Cardiac Fibroblast.
abstract: Interleukin 6 (IL-6), which is elevated in patients with congestive heart failure and acts as both a chronic marker of inflammation and an acute-phase reactant, is associated with myocardial damage. Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and could be a factor for cardiac inflammation and fibrosis. Our previous study has shown that AVP promotes the proliferation of neonatal rat cardiac fibroblasts (NRCFs) throughV1Avasopressin receptor-mediated G protein-coupled receptor kinase 2 (GRK2) signaling. In the present study, we investigated the impact of the GRK2-dependent signaling. Using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, we measured the levels of interleukin-6 (IL-6) mRNA and protein in NRCFs, respectively. Manipulation of GRK2 activation either pharmacologically or through overexpression of GRK2-ct was used to determine the role of GRK2 in regulating the effects of AVP on IL-6 production. Phosphorylation and activation of nuclear factor κ-B (NF-κB) evoked by AVP stimulation were measured by immunoblot and NF-kB luciferase reporter gene transfected in NRCFs, respectively. Present studies have found that: 1) AVP increased the level of IL-6 protein and mRNA in a dose- and time-dependent manner in NRCFs; 2) inhibition of GRK2 abolished the AVP-induced IL-6 production and NF-κB activation; and 3) blocking NF-κB signaling using the pharmacologic approach diminished AVP-induced IL-6 production. In summary, AVP induces IL-6 production of NRCFs by activating V1Areceptor signaling via a GRK2/NF-κB pathway. These findings provide a possible molecular mechanism for inflammation that occurs in heart failure and other types of cardiac stress.
authors.affiliation: Laboratory of Cardiovascular Science, Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Laboratory of Cardiovascular Science, Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Sun
authors.affiliation: Laboratory of Cardiovascular Science, Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Cardiovascular Science, Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Eran
authors.initials: E
authors.lastname: Ni
authors.affiliation: Laboratory of Cardiovascular Science, Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Cardiovascular Science, Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China Zhuwz@ntu.edu.cn.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2