title: Lack of haptoglobin results in unbalanced VEGFα/angiopoietin-1 expression, intramural hemorrhage and impaired wound healing after myocardial infarction.
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 7days 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 VEGFα transcription in Hp(-/-) mice. In line with these observations, we found increased microvascular permeability in Hp(-/-) hearts 3days 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.
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. f.arslan@umcutrecht.nl
authors.forename: Fatih
authors.initials: F
authors.lastname: Arslan
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Smeets
authors.forename: Brigitta
authors.initials: B
authors.lastname: Buttari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Profumo
authors.forename: Rachele
authors.initials: R
authors.lastname: Riganò
authors.forename: Lars
authors.initials: L
authors.lastname: Akeroyd
authors.forename: Emrah
authors.initials: E
authors.lastname: Kara
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
authors.forename: Joost P
authors.initials: JP
authors.lastname: Sluijter
authors.forename: Ben
authors.initials: B
authors.lastname: van Middelaar
authors.forename: Krista
authors.initials: K
authors.lastname: den Ouden
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Sai Kiang
authors.initials: SK
authors.lastname: Lim
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006242:Haptoglobins / Q000172:deficiency* / Q000235:genetics; D006341:Heart Rupture / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D006470:Hemorrhage / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D020556:Neutrophil Infiltration; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D058258:Serpin E2 / Q000378:metabolism; D013318:Stroke Volume; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling; D014945:Wound Healing
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D006242:Haptoglobins; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse