Tetrahydrobiopterin and endothelial dysfunction in cardiovascular diseases

Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atherosclerosis. We have reported that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired endothelial nitric oxide synthase (eNOS) activity and increased oxidative breakdown of nitric oxide (NO) due to an enhanced formation of superoxide anion, which are caused by relative deficiency of tetrahydrobiopterin (BH4) in vascular endothelial cells. Guanosine-triphosphate cyclohydrolase I, the rate-limiting enzyme in the production of BH4, is decreased in the aorta of insulin-resistant rats and supplementation of BH4 restored the endothelial function and relieved oxidative tissue damage. The BH4 treatment may evoke these benefits not only by providing eNOS with cofactor to enhance NO synthesis, but also by acting as an indirect and/or direct antioxidant to decrease superoxide anion derived from the endothelium. A further understanding of the physiological and pathological roles and their regulation may lead to new therapeutic avenues.