Heme oxygenase-1 protects against vascular constriction and proliferation.
Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.
Duckers
H J
HJ
Vascular Biology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Boehm
M
M
True
A L
AL
Yet
S F
SF
San
H
H
Park
J L
JL
Clinton Webb
R
R
Lee
M E
ME
Nabel
G J
GJ
Nabel
E G
EG
D000818:Animals; D001158:Arteries / Q000201:enzymology / Q000293:injuries / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D006152:Cyclic GMP / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D017353:Gene Deletion; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D011524:Protoporphyrins / Q000494:pharmacology; D013552:Swine; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C493957:Cdkn1a protein, mouse; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D006152:Cyclic GMP