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Metoprolol alleviates arginine vasopressin-induced cardiomyocyte hypertrophy by upregulating the AKT1-SERCA2 cascade in H9C2 cells.

ABSTRACT: Background:Arginine vasopressin (AVP) is elevated in patients with heart failure, and the increase in the AVP concentration in plasma is positively correlated with disease severity and mortality. Metoprolol (Met) is a beta blocker that is widely used in the clinic to treat pathological cardiac hypertrophy and to improve heart function. However, the specific mechanism by which Met alleviates AVP-induced pathological cardiac hypertrophy is still unknown. Our current study aimed to evaluate the inhibitory effects of Met on AVP-induced cardiomyocyte hypertrophy and the underlying mechanisms. Methods:AVP alone or AVP plus Met was added to the wild type or AKT1-overexpressing rat cardiac H9C2 cell line. The cell surface areas and ANP/BNP/?-MHC expressions were used to evaluate the levels of hypertrophy. Western bolting was used to analyze AKT1/P-AKT1, AKT2/P-AKT2, total AKT, SERCA2, and Phospholamban (PLN) expression. Fluo3-AM was used to measure the intracellular Ca2+ stores. Results:In the current study, we found that AKT1 but not AKT2 mediated the pathogenesis of AVP-induced cardiomyocyte hypertrophy. Sustained stimulation (48 h) with AVP led to hypertrophy in the H9C2 rat cardiomyocytes, resulting in the downregulation of AKT1 (0.48 fold compared to control) and SERCA2 (0.62 fold), the upregulation of PLN (1.32 fold), and the increase in the cytoplasmic calcium concentration (1.52 fold). In addition, AKT1 overexpression increased the expression of SERCA2 (1.34 fold) and decreased the expression of PLN (0.48 fold) in the H9C2 cells. Moreover, we found that Met could attenuate the AVP-induced changes in AKT1, SERCA2 and PLN expression and decreased the cytoplasmic calcium concentration in the H9C2 cells. Conclusions:Our results demonstrated that the AKT1-SERCA2 cascade served as an important regulatory pathway in AVP-induced pathological cardiac hypertrophy.

SUBMITTER: Zhao J

PROVIDER: S-EPMC7247229 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metoprolol alleviates arginine vasopressin-induced cardiomyocyte hypertrophy by upregulating the AKT1-SERCA2 cascade in H9C2 cells.

Zhao Jieqiong J Lei Yonghong Y Yang Yanping Y Gao Haibo H Gai Zhongchao Z Li Xue X

Cell & bioscience 20200524

<h4>Background</h4>Arginine vasopressin (AVP) is elevated in patients with heart failure, and the increase in the AVP concentration in plasma is positively correlated with disease severity and mortality. Metoprolol (Met) is a beta blocker that is widely used in the clinic to treat pathological cardiac hypertrophy and to improve heart function. However, the specific mechanism by which Met alleviates AVP-induced pathological cardiac hypertrophy is still unknown. Our current study aimed to evaluate ...[more]

PMID: 32489586

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Project description:Circulating levels of arginine vasopressin (AVP) are elevated during hypovolemia and during cardiac stress. AVP activates arginine vasopressin type 1A (V(1A))/G?(q)-coupled receptors in the heart and vasculature and V(2)/G?(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 mitogen-activated 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)/G?(q)-protein kinase C (PKC) and V(1A)/G protein-coupled receptor kinase (GRK)/?-arrestin signaling cascades were inhibited to dissect the pathways responsible for the protective effects of V(1A)R signaling: G?(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 ?-arrestin1 (siRNA knockdown). These studies demonstrated that both G?(q)/PKC- and GRK2/?-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 ?-arrestin1-dependent signaling. These results suggest that activation of the V(1A)R in H9c2 cells mediates protective signaling via a GRK2/?-arrestin1/ERK1/2-dependent mechanism that leads to decreased caspase 3/7 activity and enhanced survival under conditions of ischemic stress.

Dataset Information

Metoprolol alleviates arginine vasopressin-induced cardiomyocyte hypertrophy by upregulating the AKT1-SERCA2 cascade in H9C2 cells.

Publications

Metoprolol alleviates arginine vasopressin-induced cardiomyocyte hypertrophy by upregulating the AKT1-SERCA2 cascade in H9C2 cells.

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