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) throughV vasopressin 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-B) 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-B activation; and 3) blocking NF-B signaling using the pharmacologic approach diminished AVP-induced IL-6 production. In summary, AVP induces IL-6 production of NRCFs by activating V receptor signaling via a GRK2/NF-B pathway. These findings provide a possible molecular mechanism for inflammation that occurs in heart failure and other types of cardiac stress.

Impact of paroxetine on proximal β-adrenergic receptor signaling

“…However, the Food and Drug Administration-approved SSRI paroxetine was identified using a high throughput aptamer displacement assay to bind directly to GRK2 to inhibit its ability to phosphorylate rhodopsin, tubulin and thyrotropin-releasing hormone receptor, while increasing βAR-stimulated cardiomyocyte (in vitro) and cardiac (in vivo) contractility 7 . Subsequently, paroxetine has been shown to reverse cardiac dysfunction induced by either ischemia 8 or high fat diet 18 , inhibit T cell activation 19 and decrease fibroblast cytokine production 20 . Despite the increasing use of paroxetine in studies in which its effects are attributed to inhibition of receptor desensitization processes classically engaged by GRK2, such as βarr recruitment and GPCR internalization, no studies have confirmed whether it actually attenuates these responses.…”

β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK1/2-NF-κB signal pathway in murine hearts

“…Our previous study demonstrated that AVP induces IL-6 production via NF-κB signaling in neonatal rat cardiac fibroblasts [ 33 ] and cultured ARCFs (Fig. 4 ).…”

G protein‐coupled receptor kinase‐2: A potential biomarker for early diabetic cardiomyopathy

“…Other evidence of GRK2 related to DCM was provided by inhibiting the GRK2 expression. Inhibition of GRK2 increased oxygen consumption rates and ATP production, reduced the degree of myocardial remodeling, and abolished the AVP‐induced IL‐6 production and NF‐κB activation . Moreover, a very recent paper showed that GRK2 inhibition can be safely achieved with beneficial effects in diabetes, and beyond its effects on the glycemic profile, exerted the anti‐inflammatory and antioxidative effect on the heart, which indicated a potential therapeutic action on DCM …”

“…Inhibition of GRK2 increased oxygen consumption rates and ATP production, 33 reduced the degree of myocardial remodeling, 34 and abolished the AVP-induced IL-6 production and NF-κB activation. 35 Moreover, a very recent paper showed that GRK2 inhibition can be safely achieved with beneficial effects in diabetes, and beyond its effects on the glycemic profile, exerted the anti-inflammatory and antioxidative effect on the heart, which indicated a potential therapeutic action on DCM. 36 In addition to β-adrenergic receptor-mediated signaling, other mechanisms including insulin resistance, fatty acid oxidation, and cardiomyocyte oxidative stress might be involved in the relation between GRK2 and DCM.…”