Induction of heme oxygenase-1 during endotoxemia is downregulated by transforming growth factor-beta1.
Heme oxygenase (HO)-1 generates CO, a gas with vasodilatory properties, during heme metabolism. HO-1 is expressed highly in vascular tissue after endotoxin stimulation, and generation of CO through the HO-1 pathway contributes to the hemodynamic compromise of endotoxic shock. Shock related to endotoxemia is an immune-mediated process that involves the generation of proinflammatory cytokines such as interleukin (IL)-1beta. Because transforming growth factor (TGF)-beta1 is a modulator of immune-mediated inflammatory responses and it blocks the hypotension of endotoxic shock, we determined whether TGF-beta1 could be used to reduce expression of HO-1 in vascular tissue and smooth muscle cells. In a rat model of endotoxic shock, lipopolysaccharide-induced HO-1 mRNA and protein expression was reduced by TGF-beta1 in highly vascularized tissue, such as heart and lung, by Northern and Western analysis. Furthermore, TGF-beta1 downregulated HO-1 mRNA after its induction by IL-1beta in vascular smooth muscle cells in culture. TGF-beta1 also decreased HO-1 but not HO-2 protein expression in these cells. TGF-beta1 decreased HO enzyme activity induced in IL-1beta treated vascular smooth muscle cells to a level not different from that in vehicle-treated cells. These studies suggest that this downregulation of HO-1 mRNA and protein expression and decrease in IL-1beta-induced HO enzyme activity may contribute to the beneficial effect of TGF-beta1 on endotoxic shock.
Pellacani
A
A
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Mass 02115, USA.
Wiesel
P
P
Sharma
A
A
Foster
L C
LC
Huggins
G S
GS
Yet
S F
SF
Perrella
M A
MA
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D019446:Endotoxemia / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000097:blood*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012485:Salmonella typhi; D012772:Shock, Septic / Q000201:enzymology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D016212:Transforming Growth Factor beta; D006419:Heme Oxygenase (Decyclizing)