| Autor: |
Johns DG; Department of Cardiovascular Pharmacology, Metabolic Pathways Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, United States. Douglas_Johns@merck.com, Zelent D, Ao Z, Bradley BT, Cooke A, Contino L, Hu E, Douglas SA, Jaye MC |
| Jazyk: |
angličtina |
| Zdroj: |
European journal of pharmacology [Eur J Pharmacol] 2009 Mar 15; Vol. 606 (1-3), pp. 109-14. Date of Electronic Publication: 2009 Jan 10. |
| DOI: |
10.1016/j.ejphar.2008.12.030 |
| Abstrakt: |
Heme oxygenase-1 (HO) metabolizes heme to form the vasodilator carbon monoxide and antioxidant biliverdin. Upregulation of HO-1 by hemin, which is also a substrate attenuates thrombosis in rodent models, however, whether protection is due to HO-1 upregulation or to increased substrate availability is unknown. This study tested the hypothesis that treatment of mice with cobalt protoporphyrin (CoPP), a non-substrate HO-1 inducer, would protect the endothelium from laser injury. C57Bl/J6 mice were treated with vehicle, CoPP (20 mg/kg), CoPP plus the HO-1 inhibitor tin protoporphyrin (SnPP; 20 mg/kg) or SnPP alone for 18 h. Intravital microscopy was used to quantitate thrombus formation in cremaster arterioles in response to laser ablation of the endothelium. CoPP treatment inhibited thrombosis by 43% compared to vehicle (P<0.05). SnPP co-treatment negated the inhibitory effect of CoPP while SnPP alone potentiated thrombosis compared to vehicle. In CoPP-treated animals, cremaster HO-1 mRNA expression was increased 59+/-17-fold over vehicle (P<0.001). Co-treatment with CoPP+SnPP attenuated this effect by 36%, however the increase in HO-1 protein induced by CoPP was unaffected by SnPP. Induction of HO-1 by the non-substrate inducer CoPP protects against laser induced endothelial injury without the need for increased substrate. Small molecule, substrate-independent upregulation of HO-1 expression represents a feasible approach to ameliorate endothelial dysfunction in cardiovascular disease. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
Full Text from ScienceDirect