Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation.
BACKGROUND
Recent studies have demonstrated that systemic pharmacological induction of heme oxygenase-1 (HO-1), the inducible isoform of the initial and rate-limiting enzyme for heme catabolism, attenuates neointima formation after experimental vascular injury. We have now investigated the ability of localized adenovirus-mediated HO-1 (Ad-HO-1) gene delivery to modify arterial remodeling after balloon angioplasty.


RESULTS
Two weeks after balloon angioplasty in the rat carotid artery, elevated HO-1 protein was observed in the Ad-HO-1 arteries compared with those exposed to empty adenovirus (Ad-E) or to PBS. The arteries exposed to Ad-HO-1 exhibited significantly reduced neointimal area, medial wall area, neointimal area/medial wall area ratio, and neointimal thickness compared with arteries exposed to Ad-E. The Ad-E vessels showed subtle reductions in each morphometric parameter compared with PBS vessels. In a separate group of animals, concomitant treatment of Ad-HO-1 with the HO-1 inhibitor tin protoporphyrin completely restored each morphometric parameter to control levels. Arteries exposed to Ad-HO-1 demonstrated significantly increased TUNEL labeling of apoptotic nuclei and significantly decreased PCNA labeling of DNA synthesis in the medial wall 48 hours after injury.


CONCLUSIONS
These results indicate that HO-1 represents an important in vivo vasoprotective mediator that is capable of attenuating the pathophysiological remodeling response to endovascular injury and suggest that HO-1 may be a novel target for the treatment of vascular disease.
Tulis
D A
DA
Departments of Medicine, Baylor College of Medicine, and Veterans Affairs Medical Center, Houston, Texas, USA.
Durante
W
W
Liu
X
X
Evans
A J
AJ
Peyton
K J
KJ
Schafer
A I
AI
D000256:Adenoviridae / Q000235:genetics*; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D015153:Blotting, Western; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D017539:Tunica Intima / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D018809:Proliferating Cell Nuclear Antigen; D011524:Protoporphyrins; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1