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β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes

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Abstract

Selective stimulation of β3 adrenergic-receptor (β3AR) has been shown to reduce infarct size in a mouse model of myocardial ischemia/reperfusion. However, its functional long-term effect and the cardioprotective mechanisms at the level of cardiomyocytes have not been elucidated, and the impact of β3AR stimulation has not been evaluated in a more translational large animal model. This study aimed at evaluating pre-perfusion administration of BRL37344 both in small and large animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration of the β3AR agonist BRL37344 (5 μg/kg) reduced infarct size at 2-and 24-h reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) function assessed by echocardiography and cardiac magnetic resonance (CMR) was significantly improved in β3AR agonist-treated mice. Incubation with β3AR agonist (BRL37344, 7 μmol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45 days post-infarction. Pre-perfusion administration of BRL37344 (5 μg/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of β3AR agonist before reperfusion decreased infarct size and resulted in a consistent and long-term improvement in cardiac function, both in small and large animal models of myocardial ischemia/reperfusion. This protection appears to be executed through inhibition of mPTP opening in cardiomyocytes.

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Acknowledgments

We thank Dr. S. Mendez-Ferrer (CNIC) for supplying the β3AR knockout mice. We thank Rachel Dongworth, Rupa Parvin Khaton, and Virginia Zorita for the help and technical support. We also thank Ana V. Alonso for her outstanding technical support in mouse echocardiography and Gonzalo J. López and Angel Macías for theirs in swine CMR evaluations. We are grateful to the animal facilities at the CNIC and the UCL and to CNIC’s farm for their superb support with the animal care. Antonio M. Santos-Beneit provided advice in microscopy and image analysis. Simon Bartlett provided English editing.

CMR images were analyzed using dedicated software (QMass MR v.7) with support through a scientific collaboration with Medis medical imaging systems BV. Regional CMR analysis was conducted with TomTec 2D CPA MR Quantification Software with full support through scientific collaboration with Tomtec.

This work was supported by an award from the Fondo de Investigación Sanitaria to BI a (FIS 10/02268) and by the competitive grant “CNIC translational 01/2009”, also to BI.

D.S-R is supported by a CNIC-Postdoctoral Fellowship; JM.G-R and A.G-A were supported by CNIC-Cardiojoven Fellowships. The “Red de Investigación Cardiovascular (RIC)” of the Spanish Ministry of Health supports B.I (RD 12/0042/0054) and A.G-A. The “Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)” is supported by the Spanish Ministry of Economy and Competitiveness, and the Pro-CNIC Foundation.

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Authors and Affiliations

  1. Imaging, Epidemiology and Atherothrombosis Department, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain

    Jaime García-Prieto, Jose Manuel García-Ruiz, David Sanz-Rosa, Andrés Pun, Ana García-Alvarez, Leticia Fernández-Friera, Mario Nuno-Ayala, Rodrigo Fernández-Jiménez, Jesús Jimenez-Borreguero, Gonzalo Pizarro, Valentín Fuster & Borja Ibanez

  2. Cardiovascular Institute, Hospital Clínico San Carlos, Madrid, Spain

    Carlos Macaya & Borja Ibanez

  3. Hatter Cardiovascular Institute, University College London, London, UK

    Sean M. Davidson & Derek M. Yellon

  4. Cardiovascular Development and Repair Department, CNIC, Madrid, Spain

    Juan A. Bernal

  5. Advanced Imaging Unit, CNIC, Madrid, Ciber de Enfermedades Respiratorias and Universidad Complutense, Madrid, Spain

    José Luis Izquierdo-Garcia & Jesús Ruiz-Cabello

  6. Hospital Universitario Central de Asturias, Oviedo, Spain

    Jose Manuel García-Ruiz

  7. Hospital Clinic, Barcelona, Spain

    Ana García-Alvarez

  8. Hospital Universitario Monteprincipe, Madrid, Spain

    Leticia Fernández-Friera

  9. Hospital Universitario Quirón, Madrid, Spain

    Gonzalo Pizarro

  10. Zena and Michael A. Wiener CVI, Mount Sinai School of Medicine, New York, NY, USA

    Valentín Fuster

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  1. Jaime García-Prieto
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Correspondence to Borja Ibanez.

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J. García-Prieto, J. M. García-Ruiz, and D. Sanz-Rosa contributed equally.

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García-Prieto, J., García-Ruiz, J.M., Sanz-Rosa, D. et al. β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes. Basic Res Cardiol 109, 422 (2014). https://doi.org/10.1007/s00395-014-0422-0

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