The role of hyperhomocysteinemia in nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation.
Hyperhomocysteinemia (HHcy) is associated with impaired endothelial-dependent vasodilatation and increased risk of atherosclerosis and thrombosis. Here, we summarize some of our previous work on the effect of HHcy on pathways involved in endothelium-dependent vasodilatation, and present new data concerning the endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation. We showed that the 894 G>T single-nucleotide polymorphism in the human endothelial nitric oxide synthase gene (eNOS) increased the risk of recurrent venous thrombosis in individuals with elevated homocysteine levels, indicating that the pathophysiological mechanism in HHcy involves impaired NO-mediated vasodilatation. In addition, the EDHF-mediated vasodilatation of the renal artery was disturbed in diet-induced hyperhomocysteinemic rats. Interestingly, we demonstrated that pretreatment of rats with periodate-oxidized adenosine (Adox), which is an inhibitor of S-adenosylhomocysteine hydrolase, prevented the methionine-induced rise in plasma total Hcy (tHcy) levels but not the inhibition of the EDHF pathway. Furthermore, we demonstrated that S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) levels were increased in the kidneys of diet-induced HHcy rats, resulting in a decreased AdoMet:AdoHcy ratio. In addition, we demonstrated that mRNA expression of Connexin 40, which is one of the structural subunits of gap-junctions, was down-regulated in endothelial cells of HHcy rats, and correlated with elevated AdoHcy levels in kidney of these rats. These finding suggest a key role for AdoHcy in relation to decreased Cx40 mRNA expression and impaired EDHF-mediated vasodilatation of HHcy rats.
Heil
S G
SG
Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. s.heil@cukz.umcn.nl
De Vriese
A S
AS
Kluijtmans
L A J
LA
Mortier
S
S
Den Heijer
M
M
Blom
H J
HJ
D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D017629:Gap Junctions; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D016017:Odds Ratio; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation; D020246:Venous Thrombosis / Q000378:metabolism; D000097003:Gap Junction alpha-5 Protein
D001685:Biological Factors; D017630:Connexins; D009569:Nitric Oxide; D012333:RNA, Messenger; D012435:S-Adenosylhomocysteine; D000097003:Gap Junction alpha-5 Protein; C067410:endothelium-dependent hyperpolarization factor