title: Reduction of hypoxia-inducible heme oxygenase-1 in the myocardium after left ventricular mechanical support.
abstract: Left ventricular assist devices (LVAD) may improve cardiac function. The pathogenesis of this phenomenon, called 'reverse remodelling', is not completely elucidated. To examine the hypothesis that LVAD support eliminates tissue stress by reducing local hypoxia, the distribution of heme oxygenase-1 (HO-1), a stress protein inducible by hypoxia, was examined in vivo and in vitro. The immunoreactivity for HO-1 was semi-quantitatively analysed in left ventricular tissue of 23 patients (14 dilated cardiomyopathy (DCM), six ischaemic heart disease (IHD), three myocarditis/congenital heart disease) with end-stage heart failure before and after LVAD support, while two unused donor hearts served as controls. Control hearts stained almost negative for HO-1, while failing hearts showed immunoreactivity mainly in cardiomyocytes, but also in endothelial cells, some smooth muscle cells and fibroblasts. Hearts with IHD showed significantly higher HO-1 immunoreactivity than hearts with DCM or myocarditis/congenital heart disease. After LVAD support, the HO-1 content decreased significantly in the DCM and IHD group and was significantly higher in the subendocardium than in the subepicardium. In vitro, under hypoxic conditions, neonatal rat cardiomyocytes showed an increase of HO-1 protein content up to sixfold above the normal level, which returned to normal values after normoxic cultivation. Mechanical support reduces the HO-1 content of the failing heart and HO-1 is inducible in vitro under hypoxia and is reversible under normoxia. This supports the concept that restoration of cardiac normoxia by mechanical unloading, particularly in the subendocardium, may be in part responsible for the phenomenon of 'reverse remodelling'.
authors.affiliation: Institute of Pathology, University of Essen, Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.forename: Christof
authors.initials: C
authors.lastname: Schmid
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Dirk
authors.initials: D
authors.lastname: Breukelmann
authors.forename: Philip F
authors.initials: PF
authors.lastname: Halloran
authors.forename: Christian
authors.initials: C
authors.lastname: August
authors.forename: Nobuakira
authors.initials: N
authors.lastname: Takeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
authors.forename: Markus
authors.initials: M
authors.lastname: Wilhelm
authors.forename: Mario C
authors.initials: MC
authors.lastname: Deng
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
mesh_terms: D000328:Adult; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000628:therapy; D006353:Heart-Assist Devices; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008565:Membrane Proteins; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1