Antihypertensive therapy increases tetrahydrobiopterin levels and NO/cGMP signaling in small arteries of angiotensin II-infused hypertensive rats

Kang, Kyu Tae; Sullivan, Jennifer C.; Spradley, Frank T.; d’Uscio, Livius V.; Katušić, Zvonimir S.; Pollock, Jennifer S.

doi:10.1152/ajpheart.00393.2010

Cited by 26 publications

(28 citation statements)

References 45 publications

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“…Animal models of chronic BH4 supplementation. Chronic BH4 treatment has been shown to reduce angiotensin-II-induced hypertension and endothelial dysfunction (130,133), and to decrease blood pressure while improving endothelial-dependent relaxation in SHR rats (113). Renal failure-induced hypertension, due to partial nephrectomy, has also been shown to be reduced with chronic BH4 treatment (166,329), which promotes an increase of resistance artery eNOS protein expression levels (166).…”

Section: Bh4 Therapymentioning

confidence: 99%

Tetrahydrobiopterin in Cardiovascular Health and Disease

Bendall

Douglas

McNeill

et al. 2014

Antioxidants & Redox Signaling

194

187

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Tetrahydrobiopterin (BH4) functions as a cofactor for several important enzyme systems, and considerable evidence implicates BH4 as a key regulator of endothelial nitric oxide synthase (eNOS) in the setting of cardiovascular health and disease. BH4 bioavailability is determined by a balance of enzymatic de novo synthesis and recycling, versus degradation in the setting of oxidative stress. Augmenting vascular BH4 levels by pharmacological supplementation has been shown in experimental studies to enhance NO bioavailability. However, it has become more apparent that the role of BH4 in other enzymatic pathways, including other NOS isoforms and the aromatic amino acid hydroxylases, may have a bearing on important aspects of vascular homeostasis, inflammation, and cardiac function. This article reviews the role of BH4 in cardiovascular development and homeostasis, as well as in pathophysiological processes such as endothelial and vascular dysfunction, atherosclerosis, inflammation, and cardiac hypertrophy. We discuss the therapeutic potential of BH4 in cardiovascular disease states and attempt to address how this modulator of intracellular NO-redox balance may ultimately provide a powerful new treatment for many cardiovascular diseases. Antioxid. Redox Signal. 20, 3040-3077.

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Section: Bh4 Therapymentioning

confidence: 99%

Tetrahydrobiopterin in Cardiovascular Health and Disease

Bendall

Douglas

McNeill

et al. 2014

Antioxidants & Redox Signaling

194

187

View full text Add to dashboard Cite

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“…A number of studies have demonstrated that a reduced level of BH4, an essential cofactor of eNOS, contributes to NO insufficiency in hypertension [4,5]. The importance of BH4 has been underscored by the findings that eNOS uncoupling due to reduced BH4 levels leads to increased generation of superoxide anion and decreased production of NO and thus contributes to vascular oxidative stress and endothelial dysfunction [6,7]. It has been documented that loss of BH4 renders vascular endothelium dysfunctional and impairs endothelium-dependent relaxation in aorta from diabetic rats, hypertensive rats and apoE-knockout mice [6,[8][9][10].…”

mentioning

confidence: 99%

Simvastatin Ameliorates Angiotensin II-Induced Endothelial Dysfunction Through Restoration of Rho-BH4-eNOS-NO Pathway

Zhang

Wang

Xue

et al. 2011

Cardiovasc Drugs Ther

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Endothelial dysfunction contributes to the initiation and development of hypertension. We previously found that simvastatin moderately decreases blood pressure in 2-kidney-2-clip (2k2c) renal hypertension, but the precise mechanisms are still unclear. The present study was designed to examine the protective actions of simvastatin in 2k2c-evoked endothelial dysfunction and also delineate the underlying mechanisms. Here we show that 2k2c-induced elevation in plasma angiotensin II impaired acetylcholine-induced endothelium-dependent vascular relaxation, suppressed endothelial NO synthase (eNOS) activity and reduced nitric oxide (NO) production. Additionally, the levels of tetrahydrobiopterin (BH4), an essential cofactor of eNOS, as well as the activity of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for BH4 synthesis, were markedly reduced. Administration of simvastatin significantly improved acetylcholine-induced endothelium-dependent carotid arteries relaxation at 9 weeks in reno-hypertensive rats. Notably, GTPCH I activity, BH4 production, p-eNOS expression and NO levels in the vascular endothelium were elevated as a result of simvastatin administration. In cultured rat arterial endothelial cells, simvastatin restored BH4, GTPCH I activity and NO release impaired by angiotensin II, and pretreatment with mevalonate (MVA) or geranylgeranyl pyrophosphate (GGPP) abolished the beneficial effects exerted by simvastatin. Moreover, RhoA inhibitor C3 exoenzyme, Rho kinase inhibitor Y-27632 and dominant negative mutant of RhoA prevented BH4 and NO loss due to Ang II treatment. Taken together, normalization of BH4-eNOS-NO pathway at least in part accounts for the beneficial actions of simvastatin on vascular endothelium during 2k2c hypertension, and RhoA-Rho kinase pathway is involved in regulation of BH4 production.

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“…Angiotensin II reduces the expression of GCH1 and thus BH 4 de novo synthesis [82], as well as that of dihydrofolate reductase (DHFR) [7], which catalyzes the regeneration of BH 4 from its oxidized form, BH 2 . Oral supplementation with BH 4 restores NO/cGMP signaling in small arteries, and attenuates angiotensin II-induced hypertension in rats [36].…”

Section: Bh 4 Deficiency In Hypertensionmentioning

confidence: 97%