title: Intragraft heme oxygenase-1 and coronary artery disease after heart transplantation.
abstract: Peri-operative tissue injury triggers the development of Transplant Coronary Artery Disease (TCAD). Animal studies have shown that induction of heme oxygenase (HO)-1 protects the donor organ from the development of TCAD. To investigate the role of HO-1 in TCAD after clinical heart transplantation, we measured intragraft mRNA expression of HO-1, HIF-1alpha, TGF-beta, FLIP, and the Bcl-2/Bax balance. Immunohistochemical staining of HO-1 was performed to determine its origin. Myocardial biopsies taken at the end of the transplantation procedure (time 0), at 1 week and at 10 months after transplantation were studied from recipients with or without angiographic signs of accelerated TCAD, diagnosed after 1 year. At time 0, no differences in mRNA expression for any of the measured parameters were found between TCAD positive and negative patients. At 1 week, mRNA expression of HO-1 and TGF-beta was higher in grafts that developed accelerated TCAD (p=0.001 and p=0.0002). These higher mRNA levels were accompanied by a pro-apoptotic shift in Bcl-2/Bax (p=0.02), suggesting proneness for apoptosis via the mitochondrial pathway. Immunohistochemical staining showed that HO-1 was mainly produced by infiltrating macrophages. At 10 months, again HO-1 and TGF-beta levels were high in TCAD positive patients (p=0.02 and p=0.05), but the expression of apoptotic markers was comparable at this time point. Our results suggest that a higher HO-1 by macrophages in our patient population might be an adaptive response to tissue injury and inflammation, reflecting damage due to the transplantation procedure that finally results in TCAD.
authors.affiliation: Erasmus MC, University Medical Center Rotterdam, Department of Internal Medicine, Room Ee559, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. cholweg@cvmed.stanford.edu
authors.forename: Cecile T J
authors.initials: CT
authors.lastname: Holweg
authors.forename: Aggie H M M
authors.initials: AH
authors.lastname: Balk
authors.forename: Jasper
authors.initials: J
authors.lastname: Snaathorst
authors.forename: Sandra
authors.initials: S
authors.lastname: van den Engel
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Niesters
authors.forename: Alex W P M
authors.initials: AW
authors.lastname: Maat
authors.forename: P E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000328:Adult; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D016027:Heart Transplantation; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1