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Calpains mediate isoproterenol-induced hypertrophy through modulation of GRK2

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Abstract

Inhibition of the Ca2+-dependent proteases calpains attenuates post-infarction remodeling and heart failure. Recent data suggest that calpain activity is elevated in non-ischemic cardiomyopathies and that upregulation of the key cardiac G-protein-coupled receptor kinase 2 (GRK2) signaling hub promotes cardiac hypertrophy. However, the functional interactions between calpains and GRK2 in this context have not been explored. We hypothesized that calpain modulates GRK2 levels in myocardial hypertrophy of non-ischemic cause, and analyzed the mechanisms involved and the potential therapeutic benefit of inhibiting calpain activity in this situation. The oral calpain inhibitor SNJ-1945 was administered daily to male Sprague–Dawley rats or wild-type and hemizygous GRK2 mice treated with 5 mg/Kg/day isoproterenol intraperitoneally for 1 week. In isoproterenol-treated animals, calpains 1 and 2 were overexpressed in myocardium and correlated with increased calpain activity and ventricular hypertrophy. Oral co-administration of SNJ-1945 attenuated calpain activation and reduced heart hypertrophy as assessed using morphological and biochemical markers. Calpain activation induced by isoproterenol increased GRK2 protein levels, while genetic downregulation of GRK2 expression prevented isoproterenol-mediated hypertrophy independently of calpain inhibition. GRK2 upregulation was associated to calpain-dependent degradation of the GRK2 ubiquitin ligase MDM2 and to enhanced NF-κB-dependent GRK2 gene expression in correlation with calpain-mediated IĸB proteolysis. These results demonstrate that calpain mediates isoproterenol-induced myocardial hypertrophy by modulating GRK2 protein content through mechanisms involving the control of GRK2 stability and expression. Sustained calpain inhibition attenuates isoproterenol-induced myocardial hypertrophy and could be an effective therapeutic strategy to limit ventricular remodeling of non-ischemic origin.

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Funding

This study was supported by Instituto de Salud Carlos III, Spain [PI-16/00232; RETICS-RIC-RD12/0042/0021 to D.G.D., co-funded with European Regional Development Fund-FEDER contribution], by Ministerio de Economía; Industria y Competitividad (MINECO) of Spain [SAF2017-84125-R to F.M.]; by CIBERCV-Instituto de Salud Carlos III, Spain [CB16/11/00479 to D.G.D. and CB16/11/00278 to F.M, co-funded with European Regional Development Fund-FEDER contribution], and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to F.M. We also acknowledge institutional support to the CBMSO from Fundación Ramón Areces. D.A. is a recipient of a VHIR predoctoral grant.

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Authors and Affiliations

  1. Cardiovascular Diseases Research Group, Vall d’Hebron University Hospital and Research Institute, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain

    David Aluja, Javier Inserte & David Garcia-Dorado

  2. Universitat Autònoma de Barcelona, Barcelona, Spain

    David Aluja, Javier Inserte & David Garcia-Dorado

  3. CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain

    David Aluja, Javier Inserte, Petronila Penela, Catalina Ribas, Federico Mayor Jr. & David Garcia-Dorado

  4. Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC), 28049, Madrid, Spain

    Petronila Penela, Paula Ramos, Catalina Ribas, Miguel Ángel Iñiguez & Federico Mayor Jr.

  5. Instituto de Investigación Sanitaria La Princesa, 28006, Madrid, Spain

    Petronila Penela, Catalina Ribas & Federico Mayor Jr.

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  1. David Aluja
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Aluja, D., Inserte, J., Penela, P. et al. Calpains mediate isoproterenol-induced hypertrophy through modulation of GRK2. Basic Res Cardiol 114, 21 (2019). https://doi.org/10.1007/s00395-019-0730-5

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