Targeting endothelial cells with heme oxygenase-1 gene using VE-cadherin promoter attenuates hyperglycemia-mediated cell injury and apoptosis.
Risk factors for cardiovascular diseases include hyperglycemia, TNF, and reactive oxygen species (ROS), which collectively contribute to vascular endothelial cell dysfunction and apoptosis. We examined, in vascular endothelial cells, whether the selective expression of heme oxygenase-1 (HO-1) offers cytoprotection against glucose- and TNF-mediated cell death. An adenoviral vector expressing human HO-1 was constructed using a VE-cadherin (VECAD) promotor fragment, and cell-specific expression of the recombinant adenovirus was examined using endothelial and vascular smooth muscle cells. The effects of HO-1 transduction (Ad-VECAD-HO-1 gene) on HO-1 expression, HO activity, and the response to TNF and hyperglycemia were studied. Human HO-1 gene was selectively expressed in endothelial cells after infection with the Ad-VECAD-HO-1 vector. Selective expression of HO-1 prevented TNF- and hyperglycemia-mediated superoxide (O2-) formation, DNA degeneration, and upregulation of caspase, but increased the expression of pAkt and Bcl-xL, proteins responsible for endothelial dysfunction in diabetes. These results demonstrate that endothelial cell survival after oxidative stress injury may be enhanced by targeting HO-1 expression, thus blocking inflammation, apoptosis, and thereby attenuating cardiovascular risk factors.
Asija
Amit
A
Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.
Peterson
Stephen J
SJ
Stec
David E
DE
Abraham
Nader G
NG
D000256:Adenoviridae / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000235:genetics; D002196:Capillaries / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D020552:Comet Assay; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005947:Glucose / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000166:cytology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D010957:Plasmids; D011401:Promoter Regions, Genetic; D012867:Skin / Q000098:blood supply; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D005947:Glucose; D051547:Heme Oxygenase-1; D014409:Tumor Necrosis Factor-alpha; D000099152:Cadherin 5