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Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition

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Abstract

The death of myocytes occurs through different pathways, but the rupture of the plasma membrane is the key point in the transition from reversible to irreversible injury. In the myocytes, three major groups of structural proteins that link the extracellular and intracellular milieus and confer structural stability to the cell membrane: the dystrophin-associated protein complex, the vinculin–integrin link, and the spectrin-based submembranous cytoskeleton. The objective was to determine if remote ischemic preconditioning (rIPC) preserves membrane-associated cytoskeletal proteins (dystrophin and β-dystroglycan) through the inhibition of metalloproteinase type 2 (MMP-2) activity. A second objective was to describe some of the intracellular signals of the rIPC, that modify mitochondrial function at the early reperfusion. Isolated rat hearts were subjected to 30 min of global ischemia and 120 min of reperfusion (I/R). rIPC was performed by 3 cycles of ischemia/reperfusion in the lower limb (rIPC). rIPC significantly decreased the infarct size, induced Akt/GSK-3 β phosphorylation and inhibition of the MPTP opening. rIPC improved mitochondrial function, increasing membrane potential, ATP production and respiratory control. I/R increased ONOO− production, which activates MMP-2. This enzyme degrades β-dystroglycan and dystrophin and collaborates to sarcolemmal disruption. rIPC attenuates the breakdown of β-dystroglycan and dystrophin through the inhibition of MMP-2 activity. Furthermore, we confirm that rIPC activates different intracellular pathway that involves the an Akt/Gsk3β and MPTP pore with preservation of mitochondrial function.

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Funding

National Agency for Scientific and Technological Promotion [ANPCyT, PICT 2017-1447], the University of Buenos Aires [UBACyT 20020150100105BA].

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Author notes

  1. Eliana P. Bin and Tamara Zaobornyj contributed equally to this work.

Authors and Affiliations

  1. Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina

    Eliana P. Bin, Verónica D’Annunzio, Bruno Buchholz, Ricardo J. Gelpi & Martín Donato

  2. Universidad de Buenos Aires - CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina

    Eliana P. Bin, Tamara Zaobornyj, Mariana Garces, Verónica D’Annunzio, Bruno Buchholz, Timoteo Marchini, Pablo Evelson, Ricardo J. Gelpi & Martín Donato

  3. Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Físico-Química, Buenos Aires, Argentina

    Tamara Zaobornyj

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Contributions

EPB, TZ, TM and BB performed the experiments. VDA, PE, RJG and MD wrote the main manuscript text. EPB, TZ and MG prepared all the figures. All authors reviewed the manuscript.

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Correspondence to Martín Donato.

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Tamara Zaobornyj, Verónica D’Annunzio, Bruno Buchholz, Timoteo Marchini, Pablo Evelson, Ricardo J. Gelpi and Martín Donato are Members of the National Council of Scientific and Technological Research (CONICET).

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Bin, E.P., Zaobornyj, T., Garces, M. et al. Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04849-2

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