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Cardioprotection by the transfer of coronary effluent from ischaemic preconditioned rat hearts: identification of cardioprotective humoral factors

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Abstract

Ischaemic preconditioning (IPC) provides myocardial resistance to ischaemia/reperfusion (I/R) injuries. The protection afforded by IPC is not limited to the target tissue but extends to remote tissues, suggesting a mechanism mediated by humoral factors. The aim of the present study was to identify the humoral factors that are responsible for the cardioprotection induced by the coronary effluent transferred from IPC to naïve hearts. Isolated rat hearts were submitted to IPC (three cycles of 5 min I/R) before 30-min global ischaemia and 60-min reperfusion. The coronary effluent (Efl_IPC) collected during IPC was fractionated by ultrafiltration in different molecular weight ranges (<3, 3–5, 5–10, 10–30, 30–50, and >50 kDa) and evaluated for cardioprotective effects by perfusion before I/R in naïve hearts. Only the <3, 5–10 and <10 kDa fractions of hydrophobic eluate reduced I/R injuries. The cardioprotective effect of the 5–10 fraction was blocked by KATP channel blockers and a PKC inhibitor. An Efl_IPC proteomic analysis revealed 14 cytoprotection-related proteins in 4–12 kDa peptides. HSP10 perfusion protected the heart against I/R injuries. These data provide insights into the mechanisms of cardioprotection in humoral factors released by IPC. Cardioprotection is afforded by hydrophobic peptides in the 4–12 kDa size range, which activate pathways that are dependent on PKC and KATP. Fourteen 4–12 kDa peptides were identified, suggesting a potential therapeutic role for these molecules in ischaemic diseases. One of these, HSP10, identified by mass spectrometry, reduced I/R injuries and may be a potential candidate as a therapeutic target.

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Authors and Affiliations

  1. Laboratory of Cardiac Electrophysiology Antonio Paes de Carvalho, Institute of Biophysics Carlos Chagas Filho, CCS, Federal University of Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, CCS Bloco G, Ilha do Fundao, 21941-902, Rio de Janeiro, RJ, Brazil

    Leonardo Maciel, Dahienne F. de Oliveira & Jose Hamilton Matheus Nascimento

  2. Physical-Biological Laboratory Multidisciplinary Unit of Genomics Darcy Fontoura de Almeida, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Giovani C. Verissimo da Costa & Paulo M. Bisch

Authors
  1. Leonardo Maciel
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  2. Dahienne F. de Oliveira
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  3. Giovani C. Verissimo da Costa
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  4. Paulo M. Bisch
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  5. Jose Hamilton Matheus Nascimento
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Correspondence to Jose Hamilton Matheus Nascimento.

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Sources of funding

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [Grant 483639/2013-3] and the Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [Grant E-26/112.085/2012]. JHMN is a research fellow from CNPq. LM received fellowships from CNPq and FAPERJ. DFO received a fellowship from CNPq.

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The authors declare no conflicts of interest.

Electronic supplementary material

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395_2017_641_MOESM1_ESM.tif

Supplementary material 1 (TIFF 11799 kb) Figure S1 Protein–protein interactions from the STRING interaction database. Proteins smaller than 12 kDa identified by mass-spectrometry analysis of the preconditioned coronary effluent. Rat pre-pro-insulin-like growth factor (Igf1), Heat shock protein beta-7 (Hspb7), Spermatid nuclear transition protein 1 (Tnp1), Protein dpy-30 homolog (Dpy30), DCM5 protein (Dcm5), Pneumo secretory protein 2 (Scgb3a1), CAMPATH-1 antigen (Cd52), Guanine nucleotide-binding protein, gamma subunit (Gnb3), 10 kDa heat shock protein, mitochondrial (Hspe1), Protein S100-A10, Protein S100-A4, Retinal cone rhodopsin-sensitive cGMP 3’,5’-cyclic phosphodiesterase, gamma subunit (Pde6 h), Protamine-3 (Prm3), and Apolipoprotein C-II (Apoc2). proteins are represented as nodes

395_2017_641_MOESM2_ESM.tif

Supplementary material 2 (TIFF 47941 kb) Figure S2 Effect of the perfusion of different concentrations of exogenous HSP10 on post-ischaemic cardiac performance and infarct size. a Left ventricular developed pressure after 60-min reperfusion in hearts preconditioned with 0.1, 0.3, 0.5, and 1 µM HSP10. Effects of HSP10 concentrations on the end-diastolic pressure (b) and infarct size (c), after 60-min reperfusion. Representative images of TTC-stained heart sections are shown beneath each bar in the graph c. Developed pressure was expressed as percentual of the basal value. Data are mean ± SEM. Number in each colunm is n of hearts. *P < 0.05 vs. CTL

Supplementary material 3 (DOCX 16 kb)

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Supplementary material 6 (DOCX 16 kb)

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Maciel, L., de Oliveira, D.F., Verissimo da Costa, G.C. et al. Cardioprotection by the transfer of coronary effluent from ischaemic preconditioned rat hearts: identification of cardioprotective humoral factors. Basic Res Cardiol 112, 52 (2017). https://doi.org/10.1007/s00395-017-0641-2

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