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Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy

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Abstract

G protein coupled receptor kinase type 2 (GRK2) plays an important role in the development and maintenance of cardiac hypertrophy and heart failure even if its exact role is still unknown. In this study, we assessed the effect of GRK2 on the regulation of cardiac hypertrophy. In H9C2 cells, GRK2 overexpression increased atrial natriuretic factor (ANF) activity and enhanced phenylephrine-induced ANF response, and this is associated with an increase of NFκB transcriptional activity. The kinase dead mutant and a synthetic inhibitor of GRK2 activity exerted the opposite effect, suggesting that GRK2 regulates hypertrophy through upregulation of NFκB activity in a phosphorylation-dependent manner. In two different in vivo models of left ventricle hypertrophy (LVH), the selective inhibition of GRK2 activity prevented hypertrophy and reduced NFκB transcription activity. Our results suggest a previously undisclosed role for GRK2 in the regulation of hypertrophic responses and propose GRK2 as potential therapeutic target for limiting LVH.

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Conflict of interest

The authors declare that they have no conflict of interests to disclose.

Research Involving Human Participants and/or Animals

This article does not contain any studies with human participants performed by any of the authors. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by “Federico II” University Ethical committee. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Source of Funding

Progetti di rilevante interesse nazionale (PRIN)-Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) 2009 (prot. 2009EL5WBP_001), “Società italiana di ipertensione arteriosa” (SIIA) 2012 (prot. and “Fondo di Ateneo per la ricerca di base” (FARB) 2011 (prot. 300397FRB14IACCA) to G.I.

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Authors and Affiliations

  1. Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples, Italy

    Daniela Sorriento

  2. College of Physicians & Surgeons, New York Presbyterian Hospital - Manhattan, Columbia University Medical Center, New York, NY, USA

    Gaetano Santulli

  3. Department of Advanced Biomedical Science, University “Federico II” of Naples, Naples, Italy

    Antonietta Franco, Luigi Napolitano & Bruno Trimarco

  4. Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy

    Ersilia Cipolletta, Jessica Gambardella, Guido Iaccarino & Michele Ciccarelli

  5. Department of Pharmaceutical and Toxicological Chemistry, “Federico II” University of Naples, Naples, Italy

    Isabel Gomez-Monterrey

  6. Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno, Italy

    Pietro Campiglia

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  1. Daniela Sorriento
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  2. Gaetano Santulli
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Correspondence to Guido Iaccarino.

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Editor-in-Chief Jennifer L. Hall oversaw the review of this article

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Supplementary Figure 1

Effects of GRK2 on the regulation of BNP gene expression. Gene expression of BNP, a marker of hypertrophy together with ANF, was evaluated by real time PCR. GRK2 overexpression increased BNP gene expression and enhanced the response to PE. The overexpression of GRK2-DN inhibited BNP gene expression both basally and in response to PE (* p < 0.05 vs CTRL; # p < 0.05 vs PE). (JPEG 584 kb)

Supplementary Figure 2

Effects of GRK2 on angiotensin II-induced hypertrophy in vitro. To evaluate whether GRK2 inhibition was effective also in response to other hypertrophic stimuli, besides alpha-adrenergic activation, we performed a real time PCR to evaluate ANF gene expression in response to angiotensin II. The overexpression of GRK2 increased ANF gene expression and enhanced the response to angiotensin II. On the contrary, the overexpression of GRK2-DN inhibited ANF gene expression both basally and in response to angiotensin II (* p < 0.05 vs CTRL; # p < 0.05 vs angiotensin II). (JPEG 751 kb)

Supplementary Figure 3

Echocardiographic analysis of SHR rats. We report m-mode echo representative images of WKY, SHR and treated SHR groups. Y axis represents the depth (mm) and X-axis represents time (ms). (JPEG 1720 kb)

Supplementary Figure 4

Echocardiographic analysis of WKY rats. We report m-mode echo representative images of WKY, WKY treated with PE and WKY treated with PE and Ant-124. Y axis represents the depth (mm) and X-axis represents time (ms). (JPEG 3758 kb)

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Sorriento, D., Santulli, G., Franco, A. et al. Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy. J. of Cardiovasc. Trans. Res. 8, 493–502 (2015). https://doi.org/10.1007/s12265-015-9646-0

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