Tetrahydrobiopterin and Vascular Disease

Decreased endothelial NO and increased oxidative stress are both implicated in vascular disease. The role of BH4 in contributing to endothelial dysfunction has been the subject of considerable interest in recent years.

Tetrahydrobiopterin Bh4Pulmonary Hypertension Vascular Changes

Figure 3. Schematic diagram of NOS structure and function. Active NOS is a dimmer, with each monomer consisting of a reductase domain linked to an oxigenase domain. Electron are donated by NADPH, and transferred to FAD and FMN from the reductase domain of one NOS monomer, to the heme group (Fe) in the oxygenase domain of the other monomer, resulting in NO and L-citrulline synthesis and molecular oxygen. BH4 is closely bound to the heme group, serving as an electron donor and also interacts with residues from both monomers.

Figure 3. Schematic diagram of NOS structure and function. Active NOS is a dimmer, with each monomer consisting of a reductase domain linked to an oxigenase domain. Electron are donated by NADPH, and transferred to FAD and FMN from the reductase domain of one NOS monomer, to the heme group (Fe) in the oxygenase domain of the other monomer, resulting in NO and L-citrulline synthesis and molecular oxygen. BH4 is closely bound to the heme group, serving as an electron donor and also interacts with residues from both monomers.

Endothelial cells from the diabetic BB rat have reduced BH4 levels and reduced eNOS activity, which can be rescued by sepiapterin, a BH4 precursor [57]. NO-dependent vasodilatation is improved by sepiapterin in atherosclerotic aortas from ApoE-KO mice [47]. BH4 supplementation also improved vasodilatation in spontaneously hypertensive rats [14,36]. Verma et al (2002) showed that supplemental BH4 provides a novel cardio-protec-tive effect on left ventricular function, endothelial-vascular reactivity, oxi-dative damage and cardiomyocyte injury after ischemia-reperfusion injury. NOS dimerisation and coupling is reduced in hyperglycaemic human aortic endothelial cells but can be normalized by augmenting BH4, using GTPCH gene transfer [11].

In vivo studies using disease models and gene-modified animals have also suggested an important role of BH4 in cardiovascular disease. BH4 deficiency due to increased oxidative stress appears to mediate chronic DOCA-salt induced hypertension in rodents [46,94]. Cardiac hypertrophy from pressure overload induced by aortic banding has been shown to trigger myocardial eNOS uncoupling, reversible by BH4 supplementation [77]. In eNOS transgenic/ApoE-KO mice, enhanced superoxide production and accelerated atherosclerosis were prevented by pharmacological BH4 supplementation [64]. The GTPCH deficient (hph-1) mouse has reduced levels of BH4 and appears to have impaired NOS coupling [15]. Targeted overexpression of endothelial GTPCH, augmenting BH4 levels in the endothelium, can improve eNOS function and endothelial dysfunction in diabetic mice and also reduce atherosclerosis in ApoE-KO mice [2,3].

In humans, acute BH4 administration augments NO-dependent flow-mediated vasodilatation in smokers [32], and in patients with diabetes [32], hypertension [14], hypercholesterolaemia [74] or coronary artery disease [52]. Superoxide production is increased in human diabetic vessels, which is partly inhibited by a NOS inhibitor or sepiapterin [28]. However, these studies are short-term and may be confounded by non-specific antioxidant effects, given the high doses of sepiapterin used (more than hundred-fold in excess of physiological concentration). There are few data on the long-term effects of BH4 augmentation in vascular disease.

A possible association between homocysteine, a putative risk factor for vascular disease, and BH4-dependent eNOS coupling, has also recently been suggested. Homocysteine induces oxidative stress by uncoupling

When heme, BH4, Zn and L-Arg are present and attach to eNOS, coupled dimmer of eNOS can produce NO (A). Uncoupling of eNOS as a result of loss or oxidation of BH4, eNOS produce free oxygen radicals instead of NO (B).

of NOS through reduction of de novo synthesis of BH4, most likely by blunting sepiapterin reductase [79,17]. BH4 supplementation attenuates homocysteine induced endothelial dysfunction. Heterozygous knockout mice for methylenetetrahydrofolate reductase, which converts homocysteine to methionine, have mildly elevated homocysteine levels and increased aortic superoxide production. These can be inhibited by sepiapterin or L-NAME [84].

Ascorbic Acid (Vitamin C) can facilitate recycling of BH4 from BH3, thus preventing formation of inactive BH2 [65]. Heller et al (2001) found that ascorbic acid plays a role in the chemical stabilization of BH4 and that saturated ascorbic acid levels in endothelial cells are necessary to protect BH4 from oxidation and to provide optimal conditions for cellular NO synthesis.

Dihydrobiopterin (BH2), the oxidation product of BH4, may also compete with BH4 for binding to eNOS [81]. Loss of BH4 to BH2 by oxidation is a feature of the increased oxidative stress that is characteristic of vascular disease states [2,46]. However, it is still uncertain whether the ratio of BH4 /BH2 is more important than absolute BH4 levels in determining eNOS activity in vascular disease.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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