Plasma Tetrahydrobiopterin/Dihydrobiopterin Ratio A Possible Marker of Endothelial Dysfunction

Abstract

Circ J 2009; 73: 955 -962 ndothelial dysfunction (ED) plays a critical role in the initiation and progression of atherosclerosis 1,2 and is associated with risk factors for coronary artery diseases, including smoking, hypertension, hyperlipidemia, diabetes mellitus and obesity. [3][4][5][6][7] Furthermore, endothelial function was demonstrated to serve as a predictor of cardiovascular events. 8,9 Therefore, the evaluation of endothelial function is important to determine the therapeutic strategy for atherosclerotic diseases.Clinically, endothelial function has mostly been evaluated by the extent of endothelium-dependent relaxation (EDR), which is almost exclusively mediated by nitric oxide (NO). Particularly, flow-mediated vasodilatation (FMD) induced by reactive hyperemia following the release of a forearmoccluding cuff is an established method for assessing endothelial function. 10 By using this technique, the relationships between coronary risk factors and the ED have been assessed in many clinical studies, and the close linkage has been reported between endothelial function of the brachial artery and that of the coronary arteries. 11 Now it is well recognized that the extent of ED depends on the burden of coronary risk factors. 12 There have been, however, no reliable plasma markers found for ED in humans. When EDR is used as a standard representing endothelial function, only limited numbers of clinical studies have shown a correlation between a given plasma marker and EDR. 13,14 Oxidative stress has been shown as an important factor leading to ED. Oxidative stress oxidizes tetrahydrobiopterin (BH4), an essential cofactor for endothelial type NO synthase (eNOS), to its oxidative form 7, 8-dihydrobiopterin (BH2) in vascular tissue, particularly in the endothelium. 15,16 The resultant relative deficiency of BH4 causes the uncoupling of the L-arginine-NO pathway (uncoupling of eNOS), which is at least partly involved in the ED in various vascular disorders. 16,17 In certain pathological conditions such as renal failure, changes in plasma BH4 and BH2 have been reported. 18 As oxidative stress is the major factor damaging endothelial (Received September 8, 2008; revised manuscript received December 19, 2008; accepted December 25, 2008; released Background: Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4. Methods and Results:In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7, 8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients wi...

Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure

“…Thus, the relative BH4/BH2 ratio and BH2 level, rather than BH4 levels per se, appears to be central for perturbing NOS signaling. Plasma BH4/BH2 ratio also correlates with depressed endothelial function in patients with more than two cardiovascular risk factors[32]. The present data indicate that at higher doses of exogenous BH4 (and thus BH2), the intrinsic capacity to maintain BH4/BH2 ratios may become compromised, limiting net efficacy.…”

Correlation between biopterin levels and intimal-media thickness in type-2 diabetic hypertensive patients

“…It is also relevant to say that our patients were ACE/ARB-naïve and statin-naïve because those drugs have been shown to raise circulating levels of BH4 and to decrease those of BH2 [1]. It is assumed that plasma levels of biopterins reflect their endothelial levels, then; the plasma BH4/BH2 ratio can serve as a reliable marker of oxidative stress on the endothelium [4]. …”

“…Recent studies show that BH4/BH2 ratio may be even more important than the absolute BH4 levels for an adequate nitric oxide mediated endothelial function [4]. …”

Tetrahydrobiopterin in Cardiovascular Health and Disease

“…In rats, treatment with simvastatin has been shown to increase GTPCH activity, BH4 production, and nitric oxide levels in the kidney-clip model of hypertension (340). In patients with cardiovascular disease, atrovastatin has been shown to improve flow-mediated dilation in association with an increase in plasma BH4/BH2 ratio (269). Patients with coronary artery disease treated with atrovastatin have increased vascular BH4 levels, improved vascular nitric oxide bioavailability, and reduced vascular O 2 -; while ex vivo atrovastatin was found to increase GTPCH expression and activity, independently of its action on LDL (8).…”