Folic acid consumption reduces resistin level and restores blunted acetylcholine-induced aortic relaxation in obese/diabetic mice.
Folic acid supplementation provides beneficial effects on endothelial functions in patients with hyperhomocysteinemia. However, its effects on vascular functions under diabetic conditions are largely unknown. Therefore, the effect(s) of folic acid (5.7 and 71 microg/kg/day for 4 weeks) on aortic relaxation was investigated using obese/diabetic (+db/+db) mice and lean littermate (+db/+m) mice. Acetylcholine-induced relaxation in +db/+db mice was less than that observed in +db/+m mice. The reduced relaxation in +db/+db mice was restored by consumption of 71 microg/kg folic acid. Acetylcholine-induced relaxation (with and without folic acid treatment) was sensitive to N(G)-nitro-L-arginine methyl ester, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, geldanamycin and triciribine. In addition, acetylcholine-induced relaxation was attenuated by resistin. The plasma level of resistin in +db/+db mice was sevenfold higher than that measured in +db/+m mice, and the elevated plasma level of resistin in +db/+db mice was reduced by 25% after treatment with 71 microg/kg folic acid. Folic acid slightly increased the ratio of reduced glutathione to oxidized glutathione in +db/+db mice. Moreover, folic acid caused a reduction in PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression, an increase in the phosphorylation of endothelial nitric oxide synthase (eNOS(Ser1177)) and Akt(Ser473), and an enhanced interaction of heat shock protein 90 (HSP90) with eNOS in both strains, with greater magnitude observed in +db/+db mice. In conclusion, folic acid consumption improved blunted acetylcholine-induced relaxation in +db/+db mice. The mechanism may be, at least partly, attributed to enhancement of PI3K/HSP90/eNOS/Akt cascade, reduction in plasma resistin level, down-regulation of PTEN and slight modification of oxidative state.
Seto
Sai Wang
SW
Department of Pharmacology, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China.
Lam
Tsz Yan
TY
Or
Penelope Mei Yu
PM
Lee
Wayne Yuk Wai
WY
Au
Alice Lai Shan
AL
Poon
Christina Chui Wa
CC
Li
Rachel Wai Sum
RW
Chan
Shun Wan
SW
Yeung
John Hok Keung
JH
Leung
George Pak Heng
GP
Lee
Simon Ming Yuen
SM
Ngai
Sai Ming
SM
Kwan
Yiu Wa
YW
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009765:Obesity / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D052243:Resistin / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*
D052243:Resistin; D005492:Folic Acid; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000109:Acetylcholine