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Department of Cardiology, University of Heidelberg, 69115 Heidelberg, Germany
A NUMBER OF
VASCULAR PATHOLOGIES leads to an alteration of the physiology of
endothelial cells, which is generally described as endothelial
dysfunction. Endothelial dysfunction is found in basically all known
major risk factors of atherosclerosis such as hypercholesterolemia,
nicotin abuse, hypertension, and diabetes as well as in the manifest of
atherosclerosis (1, 4, 10, 16, 30, 35, 40). Furthermore,
endothelial dysfunction is a hallmark of many cardiac and coronary
pathologies, including ischemia-reperfusion injury,
inflammation, unstable angina, and acute myocardial infarction
(6, 12, 33, 38). Endothelial dysfunction is defined as an
attenuated response of coronary vessels to endothelium-dependent
vasodilators such as acetylcholine. It affects large conductance
vessels as well as the coronary microcirculation (16, 40).
Because endothelial dysfunction seems to be a general reaction of
vessels to a variety of pathophysiological stimuli, it offers a very
attractive target for a therapeutic approach. This, however, requires a
thorough understanding of the underlying pathology.
The reduction of endothelium-dependent vasodilation is mainly induced
by a decreased bioavailability of the endothelium-dependent vasodilator
nitric oxide (NO) and an increase in the activity of toxic oxygen free
radicals such as the superoxide anion O Recently, several findings have been made that lead to the hypothesis
that tetrahydrobiopterin could be a new and an effective therapeutical
option in the treatment of endothelial dysfunction. On the basis of
biochemical observations, these findings have been confirmed in in
vitro experiments with isolated cells and isolated perfused vessels and
have finally been transferred to clinical studies.
There is a close relationship between the availability of the NO
synthase cofactor tetrahydrobiopterin and NO synthesis in both
endothelial and vascular smooth muscle cells (5, 8). Biochemically, NO synthase consists of a flavin-containing reductase domain, a heme-containing oxygenase domain, and a regulatory
calmodulin-binding sequence. In addition to calcium/calmodulin, NO
synthase requires tetrahydrobiopterin as a cofactor. The precise role
of tetrahydrobiopterin in the formation of NO is still unclear, but it
is likely to have an effect as an allosteric factor and/or as a redox
cofactor (11, 17). In addition, tetrahydrobiopterin
stabilizes NO synthase and facilitates the binding to
L-arginine (29). Figure
1 schematically demonstrates the role of
tetrahydrobiopterin in the production of NO.
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Fig. 1.
Under physiological conditions, following binding of
tetrahydrobiopterin (BH4) to the oxidase domain of nitric oxide (NO)
synthase (NOS), the enzyme is activated and generates NO and
L-citrulline from L-arginine and
O2. NO diffuses rapidly to the underlying smooth muscle
cells leading to relaxation through an increase of cGMP levels.
The intracellular levels of tetrahydrobiopterin are controlled by the
generation of both NO and superoxide (9, 27). Under conditions when intracellular concentration of tetrahydrobiopterin is
reduced, NO synthase generates superoxide anions instead of NO
(2, 32, 36). Under physiological conditions, there is a
balance between endothelial production of NO and oxygen-derived free
radicals. However, in the presence of vascular risk factors or
atherosclerosis, there is a shift of this balance toward the production
of toxic oxygen-derived free radicals (22; Fig.
2). The underlying reason for the
decreased availability of tetrahydrobiopterin in endothelial
dysfunction has not yet been clarified. In endothelial cells, under
physiological conditions tetrahydrobiopterin is synthesized from GTP
via a de novo pathway by the rate-limiting enzyme GTP cyclohydrolase I
(17). Alternatively, the synthesis of tetrahydrobiopterin can occur via a so-called salvage pathway with sepiapterin as a
substrate, independent from GTP cyclohydrolase I. Therefore, it can be
speculated that a reduced expression of GTP cyclohydrolase I may be
involved in the pathology of decreased generation of tetrahydrobiopterin in atherosclerosis as has recently been shown in
coronary endothelial cells of diabetic rats (19). The
significance for human vessels needs to be clarified in further
investigations.
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Another possible explanation for the reduced availability of tetrahydrobiopterin in endothelial dysfunction is an influence of toxic radicals, which induce an alteration in cellular redox state, on the biochemistry of tetrahydrobiopterin. Toxic radicals may interact with the role of tetrahydrobiopterin as a redox agent in the synthesis of NO, affect the biosynthesis of tetrahydrobiopterin via depletion of NADPH (21), and/or prevent the recycling of tetrahydobiopterin, which is supposed to occur via flavin nucleotides (29). Furthermore, there is evidence that oxidized tetrahydrobiopterin derivatives such as 7,8-dihydrobiopterin enhance superoxide formation from endothelial NO synthase (37). Finally, it has been shown that tetrahydrobiopterin can rapidly be oxidized by peroxynitrite. This implies that if tetrahydrobiopterin levels are decreased, a concomittant increase of NO synthase-dependent generation of superoxide and peroxynitrite induces a further reduction of tetrahydrobiopterin availability (20).
An increase of both endogenous tetrahydrobiopterin production and NO synthesis through application of sepiapterin has previously been demonstrated (5, 8, 28). Furthermore, it has been shown that endothelial cell damage can be prevented by pretreatment with sepiapterin via increased intracellular levels of tetrahydrobiopterin (13).
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On the basis of the findings from experiments in cell-free media and in isolated cells, the effect of substitution with tetrahydrobiopterin or sepiapterin on endothelial dysfunction was investigated in isolated perfused vessels. We examined the influence of different tetrahydrobiopterin derivatives in isolated coronary resistance arteries from dogs, pigs, and humans. In these vessels, endothelial dysfunction was induced by either 1)ischemia-reperfusion (canine vessels) or 2) atherosclerosis following application of a cholesterol-rich diet for 4 mo (porcine vessels) or atherosclerosis resulting from the presence of coronary risk factors and confirmed by coronary angiography (human vessels). In all these pathologies, the responses of vessels to different species-dependent and endothelium-dependent agonists (dogs: calcium iononophore A-23187, serotonin, substance P; pigs: histamine, serotonin, substance P; humans: acetylcholine, histamine, serotonin) were significantly reduced. In contrast, the responses to an endothelium-independent vasodilator (sodium nitroprusside) were unaltered, indicating endothelial dysfunction. Additionally, the responses of vessels from nonischemic, nonatherosclerotic control hearts from the different groups to the endothelium-dependent vasodilators were normal.
In the dog experiments, following ischemia-reperfusion substitution of either sepiapterin or methyltetrahydropterin, a synthetic tetrahydrobiopterin, significantly improved endothelial function of coronary resistance arteries from the ischemic area as demonstrated by normalization of the effect of the different endothelium-dependent agonists. In contrast, the response of vessels from nonischemic control area or from nonischemic control hearts to the different vasodilators were not influenced by sepiapterin or methyltetrahydropterin. Additionally, treatment of control vessels with 2,4-diamino-6-hydroxypyrinidine, an inhibitor of GTP cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, significantly attenuated the effect of the endothelium-dependent vasodilators but not the effect of the endothelium-independent agonist (33).
In a similar way, substitution with sepiapterin acutely improved the reduction of vasodilation to the endothelium-dependent agonists in coronary arterioles from both humans and pigs with atherosclerosis. Sepiapterin had no such effect on the responsiveness of vessels from nonatherosclerotic control subjects (34).
These findings confirm the hypothesis that a reduced availability of tetrahydrobiopterin leading to an imbalance of intracellular levels of NO on one side and toxic radicals on the other side is involved in the development of endothelial dysfunction in different vascular pathologies.
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In a clinical study, the hypothesis was followed that
tetrahydrobiopterin deficiency contributes to the decreased
activity of NO observed in patients with hypercholesterolemia
(31). To test this hypothesis,
N
-monomethyl-L-arginine
(L-NMMA, inhibitor of basal NO activity), serotonin
(endothelium-dependent vasodilator), and nitroprusside (endothelium-independent vasodilator) were infused into the brachial artery of patients with and without hypercholesterolemia before and
after coinfusion with L-arginine or
tetrahydrobiopterin, or a combination of both. Infusion of
tetrahydrobiopterin led to a significant improvement of both the
attenuation of L-NMMA-induced vasoconstriction and the
reduction of serotonin-induced vasodilation in the hypercholesteremic
patients. In contrast, tetrahydrobiopterin infusion had no effect in
control patients without hypercholesteremia. The authors concluded that
decreased vasodilation to serotonin in hypercholesteremic subjects is
due to a reduced activity of NO secondary to an altered availability of tetrahydrobiopterin.
Similar results could be obtained in another clinical study in which the effect of tetrahydrobiopterin supplementation on endothelium-dependent vasodilation in smokers was investigated (10). Infusion with tetrahydrobiopterin significantly improved the decreased response of the brachial artery of smokers to endothelium-dependent dilators but not to an endothelium-independent agonist.
Recently, these observation could be reproduced in the coronary circulation (18). The authors found that coronary flow responses in humans with coronary artery disease can significantly be improved by application of tetrahydrobiopterin.
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The phenomenon of endothelial dysfunction has been described in different pathophysiological conditions. It can therefore be assumed that endothelial dysfunction is a generalized response of vessels to a variety of injuries. As the result of several clinical studies, it has become evident that endothelial dysfunction is of prognostic significance, for example, for patients with coronary artery disease regarding the rate of cardiac events (26). Nevertheless, there remains a lot of speculation with respect to the significance of endothelial dysfunction. To date, there are no large clinical trials demonstrating that treatment of endothelial dysfunction improves the prognosis. Furthermore, it is unknown which therapy is most effective, most safe, and most cost effective. On the basis of the available data, possible treatment options include angiotensin-converting enzyme inhibitors, statins, radical scavenging substances such as vitamin E, L-arginine, and tetrahydrobiopterin. These substances have been shown to improve endothelial dysfunction via different mechanisms, finally increasing the availability of NO and decreasing the presence of toxic radicals (4, 14, 34, 39). However, there are still controversies that need to be resolved. For example, whereas treatment with statins has been found to improve the prognosis of patients with coronary artery disease in some studies (24, 25), there is a recent study demonstrating that, although endothelial dysfunction is attenuated by statins, there is no impact on the prognosis (39).
From the theoretical background and the very fundamental data demonstrating the important role of tetrahydrobiopterin for the synthesis of NO and for the regulation of the NO-producing enzyme NO synthase, a manipulation of the metabolism of tetrahydrobiopterin may be promising with regard to the treatment of endothelial dysfunction in the future.
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ACKNOWLEDGEMENTS |
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This paper was supported in part by a grant from the Deutsche Forschungsgemeinschaft.
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. P. Tiefenbacher, Dept. of Cardiology, Univ. of Heidelberg, Bergheimerstrasse 58, 69115 Heidelberg, Germany (E-mail: ctiefenbacher{at}med.uni-heidelberg.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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