Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling.
To examine the role of heme oxygenase (HO)-1 in the pathophysiology of vascular diseases, we generated mice deficient in both HO-1 and apolipoprotein E (HO-1-/-apoE-/-). Despite similar total plasma cholesterol levels in response to hypercholesterolemia, HO-1-/-apoE-/- mice, in comparison with HO-1+/+apoE-/- mice, had an accelerated and more advanced atherosclerotic lesion formation. In addition to greater lipid accumulation, these advanced lesions from HO-1-/-apoE-/- mice contained macrophages and smooth muscle alpha-actin-positive cells. We further tested the role of HO-1 on neointimal formation in a mouse model of vein graft stenosis. Autologous vein grafts in HO-1-/- mice showed robust neointima consisting of alpha-actin-positive vascular smooth muscle cells (VSMC) 10 days after surgery in comparison to the smaller neointima formed in autologous vein grafts in HO-1+/+ mice. However, at 14 days after surgery, the neointima from composite vessels of HO-1-/- mice was composed mainly of acellular material, indicative of substantial VSMC death. VSMC isolated from HO-1-/- mice were susceptible to oxidant stress, leading to cell death. Our data demonstrate that HO-1 plays an essential protective role in the pathophysiology of atherosclerosis and vein graft stenosis.
Yet
Shaw-Fang
SF
Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. syet@rics.bwh.harvard.edu.
Layne
Matthew D
MD
Liu
Xiaoli
X
Chen
Yen-Hsu
YH
Ith
Bonna
B
Sibinga
Nicholas E S
NE
Perrella
Mark A
MA
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002114:Calcinosis / Q000209:etiology / Q000473:pathology; D016923:Cell Death; D006083:Graft Occlusion, Vascular / Q000209:etiology* / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D018384:Oxidative Stress
D001057:Apolipoproteins E; D008565:Membrane Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse