Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor.
Elevated plasma homocysteine accelerates myointimal hyperplasia and luminal narrowing after carotid endarterectomy. N-methyl D aspartate receptors (NMDAr) in rat cerebrovascular cells are involved in homocysteine uptake and receptor-mediated stimulation. In the vasculature, NMDAr subunits (NR1, 2A-2D) have been identified by sequence homology in rat aortic endothelial cells. Exposure of these cells to homocysteine increased expression of receptor subunits, an effect that was attenuated by dizocilpine (MK801), a noncompetitive NMDA inhibitor. The objective of this study was to investigate the existence of an NMDAr in rat vascular smooth muscle (A7r5) cells, and also the effect of homocysteine on vascular dysregulation as mediated by this receptor. Subunits of the NMDAr (NR1, 2A-2D) were detected in the A7r5 cells by using the reverse transcriptase polymerase chain reaction and Western blotting. Homocysteine induced an increase in A7r5 cell proliferation, which was blocked by MK801. Homocysteine, in a dose and time dependent manner, increased expression of matrix metallinoproteinase-9 and interleukin-1beta, which have been implicated in vascular smooth muscle cell migration and/or proliferation. Homocysteine reduced the vascular elaboration of nitric oxide and increased the elaboration of the nitric oxide synthase inhibitor, asymmetric dimethylarginine. All of these homocysteine mediated effects were inhibited by MK801. NMDAr exist in vascular smooth muscle cells and appear to mediate, at least in part, homocysteine-induced dysregulation of vascular smooth muscle cell functions.
Qureshi
Irfan
I
Department of Surgery, Division of Vascular Surgery, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
Chen
Hongjiang
H
Brown
Aliza T
AT
Fitzgerald
Ryan
R
Zhang
Xingjian
X
Breckenridge
Julie
J
Kazi
Rafi
R
Crocker
Amy J
AJ
Stühlinger
Markus C
MC
Lin
Kenneth
K
Cooke
John P
JP
Eidt
John F
JF
Moursi
Mohammed M
MM
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D018929:Cell Culture Techniques; D002465:Cell Movement; D049109:Cell Proliferation; D006710:Homocysteine / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
D007375:Interleukin-1; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D006710:Homocysteine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D020780:Matrix Metalloproteinase 9