Heme oxygenase 1 determines atherosclerotic lesion progression into a vulnerable plaque.
BACKGROUND
The molecular regulation for the transition from stable to vulnerable plaque remains to be elucidated. Heme oxygenase 1 (HO-1) and its metabolites have been implicated in the cytoprotective defense against oxidative injury in atherogenesis. In this study, we sought to assess the role of HO-1 in the progression toward plaque instability in carotid artery disease in patients and in a murine model of vulnerable plaque development.


RESULTS
Atherectomy biopsy from 112 patients with clinical carotid artery disease was collected and stratified according to characteristics of plaque vulnerability. HO-1 expression correlated closely with features of vulnerable human atheromatous plaque (P<0.005), including macrophage and lipid accumulation, and was inversely correlated with intraplaque vascular smooth muscle cells and collagen deposition. HO-1 expression levels correlated with the plaque destabilizing factors matrix metalloproteinase-9, interleukin-8, and interleukin-6. Likewise, in a vulnerable plaque model using apolipoprotein E(-/-) mice, HO-1 expression was upregulated in vulnerable versus stable lesions. HO-1 induction by cobalt protoporphyrin impeded lesion progression into vulnerable plaques, indicated by a reduction in necrotic core size and intraplaque lipid accumulation, whereas cap thickness and vascular smooth muscle cells were increased. In contrast, inhibition of HO-1 by zinc protoporphyrin augmented plaque vulnerability. Plaque stabilizing was prominent after adenoviral transduction of HO-1 compared with sham virus-treated animals, providing proof that the observed effects on plaque vulnerability were HO-1 specific.


CONCLUSIONS
Here we demonstrate in a well-defined patient group and a murine vulnerable plaque model that HO-1 induction reverses plaque progression from a vulnerable plaque to a more stable phenotype as part of a compensatory atheroprotective response.
Cheng
Caroline
C
Molecular Cardiology Laboratory, Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center Rotterdam, Rotterdam 3015 CE, The Netherlands.
Noordeloos
Annemarie M
AM
Jeney
Viktoria
V
Soares
Miguel P
MP
Moll
Frans
F
Pasterkamp
Gerard
G
Serruys
Patrick W
PW
Duckers
Henricus J
HJ
D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology; D014162:Transfection
D001057:Apolipoproteins E; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D003094:Collagen; D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9