Arginine Vasopressin Enhances Cell Survival via a G Protein–Coupled Receptor Kinase 2/β-Arrestin1/Extracellular-Regulated Kinase 1/2–Dependent Pathway in H9c2 Cells

Abstract

Circulating levels of arginine vasopressin (AVP) are elevated during hypovolemia and during cardiac stress. AVP activates arginine vasopressin type 1A (V 1A )/Ga q -coupled receptors in the heart and vasculature and V 2 /Ga s -coupled receptors in the kidney. However, little is known regarding the signaling pathways that influence the effects of V 1A receptor (V 1A R) activation during cellular injury. Using hypoxia-reoxygenation (H/R) as a cell injury model, we evaluated cell survival and caspase 3/7 activity in H9c2 myoblasts after treatment with AVP. Pretreatment of H9c2 cells with AVP significantly reduced H/R-induced cell death and caspase 3/7 activity, effects that were blocked via both selective V 1A R inhibition and mitogenactivated protein kinase (MEK1/2) inhibition. AVP increased extracellular-regulated kinase 1/2 (ERK1/2) phosphorylation in a concentration-dependent manner that was sensitive to MEK1/2 inhibition and V 1A R inhibition, but not V 1B R or V 2 R inhibition. Discrete elements of the V 1A /Ga q -protein kinase C (PKC) and V 1A /G protein-coupled receptor kinase (GRK)/b-arrestin signaling cascades were inhibited to dissect the pathways responsible for the protective effects of V 1A R signaling: Ga q (overexpression of Gq-I-ires-green fluorescent protein), PKC (administration of Ro 31-82425; 2-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide, HCl, bisindolylmaleimide X, HCl), GRK2 [C-terminal GRK2 peptide overexpression and small interfering RNA (siRNA) knockdown], GRK5 (siRNA knockdown), and b-arrestin1 (siRNA knockdown). These studies demonstrated that both Ga q /PKC-and GRK2/b-arrestin1-dependent V 1A R signaling were capable of inducing ERK1/2 phosphorylation in response to AVP stimulation. However, AVP-mediated protection against H/R was elicited only via GRK2-and b-arrestin1-dependent signaling. These results suggest that activation of the V 1A R in H9c2 cells mediates protective signaling via a GRK2/b2 arrestin1/ERK1/2-dependent mechanism that leads to decreased caspase 3/7 activity and enhanced survival under conditions of ischemic stress.

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

“…Taken together these data suggest that changes in GRK5 are associated with the pathophysiology of severe neuropsychiatric illnesses associated with cognitive impairment. GRK5 abnormalities are also associated with cocaine administration, major depressive disorder, as well as behavioral hypersensitivity, consistent with the central role(s) of this molecule for linking GPCR activation with intracellular signaling processes (Bychkov et al, 2011a; Erdtmann-Vourliotis et al, 2001; Franklin and Carrasco, 2013; Gainetdinov et al, 1999; Ji et al, 2013; Kara et al, 2006; Luo et al, 2008; Ren et al, 2005; Shenoy et al, 2006; Zheng et al, 2012; Zhu et al, 2004; Zhu et al, 2013). …”

Vasopressin attenuates ischemia–reperfusion injury via reduction of oxidative stress and inhibition of mitochondrial permeability transition pore opening in rat hearts

“…In the previous study we have shown that AVP (0.03 mg/rat) has protective effects on ischemia/reperfusion (I/R) induced myocardial injury in rat heart (Nazari et al, 2011). Interestingly, other study confirmed the protective effects of AVP in low dose on myocardial injury of the ischemic reperfused heart (Pelletier et al, 2013;Zhu et al, 2013). Also vasopressin infusion is cardioprotective in models of myocardial ischemia (Okamura et al, 1999) and in patients with postcardiotomy shock (Dunser et al, 2002).…”

“…Vasopressin or arginine vasopressin (AVP) is essential for cardiovascular homeostasis (Holmes et al, 2001). Circulating levels of AVP, which are elevated during hypovolemia and during cardiac stress, mediate important physiological functions such as osmotic regulation, vasoconstriction, and release of adrenocorticotropic hormone (ACTH) (Zhu et al, 2013). In the previous study we have shown that AVP (0.03 mg/rat) has protective effects on ischemia/reperfusion (I/R) induced myocardial injury in rat heart (Nazari et al, 2011).…”

Bias Analyses of Preclinical and Clinical D2 Dopamine Ligands: Studies with Immediate and Complex Signaling Pathways

“…The next complex signaling pathway analyzed was D2R-mediated ERK phosphorylation. b-Arrestins are involved in ERK phosphorylation downstream of several GPCRs (Lefkowitz and Shenoy, 2005;Zhu et al, 2013). However, it has been suggested that the D2R-mediated ERK phosphorylation is a G protein-mediated event that is not dependent on b-arrestins (Quan et al, 2008).…”