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Articles in PresS, published online ahead of print February 28, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00935.2001
Submitted on October 30, 2001
Accepted on February 12, 2002
1 Medicine, University of Calgary, Calgary, Alberta, Canada
2 Medicine, University of Toronto, Calgary, Alberta, Canada
3 Molecular Biology, The Scripps Research Insititute, LA Jolla, California, USA
* To whom correspondence should be addressed. E-mail: subodh.verma{at}sympatico.ca.
The present study was designed to investigate the interaction between 5-methyltetrahydrofolate and tetrahydrobiopterin in modulating endothelial function. Tetrahydrobiopterin is a critical cofactor for nitric oxide synthase and maintains this enzyme as a nitric oxide vs. superoxide-producing enzyme. The structure of 5-methyltetrahydrofolate is similar to tetrahydrobiopterin and both agents have been shown to improve endothelium-dependent vasodilatation. We hypothesized that 5-methyltetrahydrofolate interacts with nitric oxide synthase in a fashion analogous, yet independent of tetrahydrobiopterin to improve endothelial function. We demonstrate that 5-methyltetrahydrofolate binds the active site of nitric oxide synthase and mimics the orientation of tetrahydrobiopterin. Furthermore, 5-methyltetrahydrofolate attenuates superoxide production (induced by inhibition of tetrahydrobiopterin synthesis), and improves endothelial function in aortae isolated from tetrahydrobiopterin-deficient rats. We suggest that 5-methyltetrahydrofolate directly interacts with nitric oxide synthase to promote nitric oxide (vs. superoxide) production and improve endothelial function. 5-methyltetrahydrofolate may represent an important strategy for intervention aimed at improving tetrahydrobiopterin bioavailability.
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