Tetrahydrobiopterin attenuates homocysteine induced endothelial dysfunction.
Homocysteine is an independent risk factor for atherosclerotic vascular disease. It impairs endothelial function via increasing superoxide production and quenching nitric oxide (NO) release. Tetrahydrobiopterin (BH4) is a critical cofactor that couples nitric oxide synthase and facilitates the production of nitric oxide (vs. superoxide anions). In the first study, the effects of hyperhomocysteinemia (0.1 mM, 3 h) on endothelium-dependent vasorelaxation to ACh and A23187 were examined in isolated segments of rat aortae in the presence or absence of BH4 (0.1 mM). In the second study, the effects of hyperhomocysteinemia (24 h) on nitric oxide production and superoxide release (using lucigenin chemiluminescence) were studied in human umbilical vein endothelial cells in the absence or presence of BH4 (10 microM). Homocysteine incubation impaired receptor-dependent and -independent endothelial function to ACh and A23187. This effect was attenuated by BH4. Furthermore, homocysteine exposure increased superoxide production and impaired agonist-stimulated nitric oxide release. These effects were attenuated by BH4 (p < 0.05). Hyperhomocysteinemia impairs endothelial function, in part due to a diminished bioavailability of BH4 with resultant uncoupling of nitric oxide synthase. BH4 may represent an important target for strategies aimed at improving endothelial dysfunction secondary to hyperhomocysteinemia.
Dhillon
Bikramjit
B
Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
Badiwala
Mitesh V
MV
Maitland
Andrew
A
Rao
Vivek
V
Li
Shu-Hong
SH
Verma
Subodh
S
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D006710:Homocysteine; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D000001:Calcimycin; C003402:sapropterin; D000109:Acetylcholine