L-Homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells.
Atherothrombotic cardiovascular disease associated with hyperhomocysteinemia has been proposed to result, at least in part, from increased vascular oxidative stress. Here we characterize one mechanism by which homocyteine may induce a vascular cell type-specific oxidative stress. Our results show that L-homocysteine at micromolar levels stereospecifically increases lipid peroxidation in cultured endothelial cells, but not in vascular smooth muscle cells or when medium is incubated in the absence of cells. Consistent with these observations, homocysteine also increases the formation of intracellular reactive oxygen species. The pro-oxidant effect of homocysteine can be fully replicated by an equivalent concentration of homocystine (i.e., an oxidized form of homocysteine), but not with cysteine or glutathione. Homocyst(e)ine-dependent lipid peroxidation is independent of H(2)O(2) and alterations in glutathione peroxidase activity, but dependent on superoxide. Mechanistically, the pro-oxidant effect of homocysteine appears to involve endothelial nitric oxide synthase (eNOS), as it is blocked by the eNOS inhibitor L-N(G)-nitroarginine methyl ester. Thus, homocyst(e)ine actively promotes oxidative stress in endothelial cells via an eNOS-dependent mechanism.
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University, School of Medicine, Boston, MA 02118, USA.
Stanley J
SJ
Heydrick
Norbert
N
Weiss
Shane R
SR
Thomas
Andre P
AP
Cap
David R
DR
Pimentel
Joseph
J
Loscalzo
John F
JF
Keaney
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D006711:Homocystine / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000201:enzymology*; D015227:Lipid Peroxidation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III
D004791:Enzyme Inhibitors; D006710:Homocysteine; D006711:Homocystine; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005978:Glutathione; D003545:Cysteine; D019331:NG-Nitroarginine Methyl Ester