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Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures

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Abstract

The demonstration that caveolin-3 overexpression reduces myocardial ischemia/reperfusion injury and our own finding that multiprotein signaling complexes increase in mitochondria in association with caveolin-3 levels, led us to investigate the contribution of caveolae-driven extracellular signal-regulated kinases 1/2 (ERK1/2) on maintaining the function of cardiac mitochondrial subpopulations from reperfused hearts subjected to postconditioning (PostC). Rat hearts were isolated and subjected to ischemia/reperfusion and to PostC. Enhanced cardiac function, reduced infarct size and preserved ultrastructure of cardiomyocytes were associated with increased formation of caveolar structures, augmented levels of caveolin-3 and mitochondrial ERK1/2 activation in PostC hearts in both subsarcolemmal (SSM) and interfibrillar (IFM) subpopulations. Disruption of caveolae with methyl-β-cyclodextrin abolished cardioprotection in PostC hearts and diminished pho-ERK1/2 gold-labeling in both mitochondrial subpopulations in correlation with suppression of resistance to permeability transition pore opening. Also, differences between the mitochondrial subpopulations in the setting of PostC were evaluated. Caveolae disruption with methyl-β-cyclodextrin abolished the cardioprotective effect of postconditioning by inhibiting the interaction of ERK1/2 with mitochondria and promoted decline in mitochondrial function. SSM, which are particularly sensitive to reperfusion damage, take advantage of their location in cardiomyocyte boundary and benefit from the cardioprotective signaling driven by caveolae, avoiding injury propagation.

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Acknowledgements

The authors thank Rocio Torrico-Lavayen for technical assistance.

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Authors and Affiliations

  1. Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano No. 1, Sección XVI, 14080, Ciudad de México, México

    Wylly Ramsés García-Niño, Francisco Correa, Julia Isabel Rodríguez-Barrena, Mabel Buelna-Chontal & Cecilia Zazueta

  2. Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, 14000, Ciudad de México, México

    Juan Carlos León-Contreras & Rogelio Hernández-Pando

  3. Departamento de Patología, Instituto Nacional de Cardiología “Ignacio Chávez”, 14080, Ciudad de México, México

    Elizabeth Soria-Castro

  4. Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, México

    José Pedraza-Chaverri

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  1. Wylly Ramsés García-Niño
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  2. Francisco Correa
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  3. Julia Isabel Rodríguez-Barrena
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  4. Juan Carlos León-Contreras
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  6. Elizabeth Soria-Castro
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  7. Rogelio Hernández-Pando
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  8. José Pedraza-Chaverri
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  9. Cecilia Zazueta
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Correspondence to Wylly Ramsés García-Niño or Cecilia Zazueta.

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All authors in this work gave their informed consent prior to their inclusion in the study. The manuscript does not contain clinical studies or patient data.

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This work was supported by Grant 177527 to CZ, 181593 to FC and 220046 to JP-Ch from the National Council of Science and Technology (CONACYT), Mexico.

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García-Niño, W.R., Correa, F., Rodríguez-Barrena, J.I. et al. Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures. Basic Res Cardiol 112, 15 (2017). https://doi.org/10.1007/s00395-017-0607-4

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