Lack of haptoglobin results in unbalanced VEGF alpha/angiopoietin-1 expression, intramural hemorrhage and impaired wound healing after myocardial infarction

F. Arslan, M.B. Smeets, B. Buttari, E. Profumo, R. Rigano, L. Akeroyd, E. Kara, L. Timmers, J.P.G. Sluijter, B.J. van Middelaar, K. den Ouden, G. Pasterkamp, S.K. Lim, D.P.V. de Kleijn

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Decreased haptoglobin (Hp) functionality due to allelic variations is associated with worsened outcome in patients after myocardial infarction (MI). However, mechanisms through which haptoglobin deficiency impairs cardiac repair remain to be elucidated. In the present study, we identified novel molecular alterations mediated by Hp involved in early and late cardiac repair responses after left coronary artery ligation in Hp(-/-) and wild-type (WT) mice. We observed a higher mortality rate in Hp(-/-) mice despite similar infarct size between groups. Deaths were commonly caused by cardiac rupture in Hp(-/-) animals. Histological analysis of 3 and 7 days old non-ruptured infarcted hearts revealed more frequent and more severe intramural hemorrhage and increased leukocyte infiltration in Hp(-/-) mice. Analyses of non-ruptured hearts revealed increased oxidative stress, reduced PAI-1 activity and enhanced VEGF alpha transcription in Hp(-/-) mice. In line with these observations, we found increased microvascular permeability in Hp(-/-) hearts 3 days after infarction. In vitro, haptoglobin prevented hemoglobin-induced oxidative stress and restored VEGF/Ang-1 balance in endothelial cell cultures. During long-term follow-up of the surviving animals, we observed altered matrix turnover, impaired scar formation and worsened cardiac function and geometry in Hp(-/-) mice. In conclusion, haptoglobin deficiency severely deteriorates tissue repair and cardiac performance after experimental MI. Haptoglobin plays a crucial role in both short- and long-term cardiac repair responses by reducing oxidative stress, maintaining microvascular integrity, myocardial architecture and proper scar formation. (c) 2012 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)116-128
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume56
DOIs
Publication statusPublished - Mar 2013

Keywords

  • Angiopoietin-1
  • Animals
  • Capillary Permeability
  • Coronary Vessels
  • Gene Expression
  • Haptoglobins
  • Heart Rupture
  • Hemorrhage
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction
  • Myocardium
  • Neutrophil Infiltration
  • Oxidation-Reduction
  • Oxidative Stress
  • Serpin E2
  • Stroke Volume
  • Vascular Endothelial Growth Factor A
  • Ventricular Remodeling
  • Wound Healing
  • Journal Article
  • Research Support, Non-U.S. Gov't

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