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Drug Delivery and Translational Research

, Volume 9, Issue 5, pp 935–944 | Cite as

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

  • María del Rosario Bauzá
  • Carlos Sebastián Giménez
  • Paola Locatelli
  • Andrea De Lorenzi
  • Anna Hnatiuk
  • Maurizio C. Capogrossi
  • Alberto Crottogini
  • Luis Cuniberti
  • Fernanda Daniela OleaEmail author
Original Article

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.

Keywords

HMGB1 Cardioprotection Acute myocardial infarction Sheep 

Notes

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 information

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.

Compliance with ethical standards

Conflict of interest

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.

Supplementary material

13346_2019_628_MOESM1_ESM.docx (14 kb)
ESM 1 (DOCX 13.6 kb)

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Copyright information

© Controlled Release Society 2019

Authors and Affiliations

  • María del Rosario Bauzá
    • 1
  • Carlos Sebastián Giménez
    • 1
  • Paola Locatelli
    • 1
  • Andrea De Lorenzi
    • 2
  • Anna Hnatiuk
    • 1
  • Maurizio C. Capogrossi
    • 3
  • Alberto Crottogini
    • 1
  • Luis Cuniberti
    • 1
  • Fernanda Daniela Olea
    • 1
    Email author
  1. 1.Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)Universidad Favaloro-CONICETBuenos AiresArgentina
  2. 2.Hospital Universitario de la Fundación FavaloroBuenos AiresArgentina
  3. 3.Division of CardiologyJohns Hopkins Bayview Medical CenterBaltimoreUSA

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