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High-dose intramyocardial HMGB1 induces long-term cardioprotection in sheep with myocardial infarction

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Abstract

In rodents with acute myocardial infarction (AMI), high mobility group box 1 (HMGB1) injection has produced controversial results. Given the lack of data in large mammals, we searched the dose that would promote angiogenesis and expression of specific regenerative genes in sheep with AMI (protocol 1) and, subsequently, use this dose to study long-term effects on infarct size and left ventricular (LV) function (protocol 2). Protocol 1: Sheep with AMI received 250 μg (high-dose, n = 7), 25 μg (low-dose, n = 7) HMGB1, or PBS (placebo, n = 7) in 10 intramyocardial injections (0.2 ml each) in the peri-infarct area. Seven days later, only the high-HMGB1-dose group exhibited higher microvascular densities, Ki67-positive cardiomyocytes, and overexpression of VEGF, Ckit, Tbx20, Nkx2.5, and Gata4. Protocol 2: Sheep with AMI received HMGB1 250 μg (n = 6) or PBS (n = 6). At 60 days, HMGB1-treated sheep showed smaller infarcts (8.5 ± 2.11 vs. 12.2 ± 1.97% LV area, P < 0.05, ANOVA-Bonferroni) and higher microvascular density (capillaries, 1798 ± 252 vs. 1266 ± 250/mm2; arterioles, 18.3 ± 3.9 vs. 11.7 ± 2.2/mm2; both P < 0.01). Echocardiographic LV ejection fraction, circumferential shortening, and wall thickening increased from day 3 to 60 with HMGB1 (all P < 0.05). Conclusion: in ovine AMI, high-dose HMGB1 induces angio-arteriogenesis, reduces infarct size, and improves LV function at 2 months post-treatment.

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Acknowledgments

We thank veterinarians María Inés Besansón and Pedro Iguain for anesthetic management and animal house assistants Juan Carlos Mansilla, Osvaldo Sosa, and Juan Ocampo for dedicated care of the animals. We also thank Julio Martínez, Fabián Gauna, and Rosana Valverdi for technical help.

Funding

Supported by grant 2012-1729 from the National Agency for the Promotion of Science and Technology (ANPCyT), Ministry of Science, Technology and Innovative Production (MINCyT) of Argentina.

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Author notes

  1. Luis Cuniberti and Fernanda Daniela Olea contributed equally to this work.

Authors and Affiliations

  1. Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Universidad Favaloro-CONICET, Solís 453, C1078AAI, Buenos Aires, Argentina

    María del Rosario Bauzá, Carlos Sebastián Giménez, Paola Locatelli, Anna Hnatiuk, Alberto Crottogini, Luis Cuniberti & Fernanda Daniela Olea

  2. Hospital Universitario de la Fundación Favaloro, Buenos Aires, Argentina

    Andrea De Lorenzi

  3. Division of Cardiology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA

    Maurizio C. Capogrossi

Authors
  1. María del Rosario Bauzá
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  2. Carlos Sebastián Giménez
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  9. Fernanda Daniela Olea
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Correspondence to Fernanda Daniela Olea.

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The authors declare that they have no conflict of interest.

Ethical standards

All procedures were carried out in accordance with the Guide for Care and Use of Laboratory Animals, published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and approved and monitored by the Laboratory Animal Care and Use Committee (CICUAL) of the Favaloro University (approval # DCT0157-12). The manuscript does not contain clinical studies or patient data.

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Key messages

• HMGB1 reduces infarct size and preserves LV function in ovine myocardial infarction

• HMGB1 increases capillary and arteriolar density in the infarct border zone

• HMGB1 induces overexpression of angiogenic and cardiomyogenic genes

• HMGB1-treated sheep show 15-fold higher density of cycling cardiomyocytes vs. placebo

• High-dose HMGB1 induces long-term cardioprotection in a translational model of AMI

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Bauzá, M.d.R., Giménez, C.S., Locatelli, P. et al. High-dose intramyocardial HMGB1 induces long-term cardioprotection in sheep with myocardial infarction. Drug Deliv. and Transl. Res. 9, 935–944 (2019). https://doi.org/10.1007/s13346-019-00628-z

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