Gene Transfer of Human Guanosine 5′-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension

Zheng, Jie; Yang, Xiang Qun; Lookingland, Keith J.; Fink, Gregory D.; Heßlinger, Christian; Kapatos, Gregory; Kovesdi, Imre; Chen, Alex F.

doi:10.1161/01.cir.0000089082.40285.c3

Cited by 126 publications

(97 citation statements)

References 49 publications

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“…Previous studies demonstrated that inhibition of GTP-CH I impaired endothelium-dependent relaxation (26). Overexpression of GTP-CH I was found partially effective in improving endothelial function in diabetic (27) and hypertensive rodents (28). However, functional regulation of the salvage enzyme DHFR, which could be more crucial in determining H 4 B and NO…”

Section: Discussionmentioning

confidence: 97%

Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase

Chalupský

Cai

2005

Proc. Natl. Acad. Sci. U.S.A.

302

306

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Recent studies demonstrate that oxidative inactivation of tetrahydrobiopterin (H4B) may cause uncoupling of endothelial nitric oxide synthase (eNOS) to produce superoxide (O 2 •؊ ). H4B was found recyclable from its oxidized form by dihydrofolate reductase (DHFR) in several cell types. Functionality of the endothelial DHFR, however, remains completely unknown. Here we present findings that specific inhibition of endothelial DHFR by RNA interference markedly reduced endothelial H4B and nitric oxide (NO • ) bioavailability. Furthermore, angiotensin II (100 nmol͞liter for 24 h) caused a H4B deficiency that was mediated by H2O2-dependent downregulation of DHFR. This response was associated with a significant increase in endothelial O 2•؊ production, which was abolished by eNOS inhibitor N-nitro-L-arginine-methyl ester or H2O2 scavenger polyethylene glycol-conjugated catalase, strongly suggesting H2O2-dependent eNOS uncoupling. Rapid and transient activation of endothelial NAD(P)H oxidases was responsible for the initial burst production of O 2 • (Rac1 inhibitor NSC 23766 but not an N-nitro-L-arginine-methyl ester-attenuated ESR O 2•؊ signal at 30 min) in response to angiotensin II, preceding a second peak in O 2•؊ production at 24 h that predominantly depended on uncoupled eNOS. Overexpression of DHFR restored NO • production and diminished eNOS production of O 2•؊ in angiotensin II-stimulated cells. In conclusion, these data represent evidence that DHFR is critical for H4B and NO • bioavailability in the endothelium. Endothelial NAD(P)H oxidase-derived H2O2 down-regulates DHFR expression in response to angiotensin II, resulting in H4B deficiency and uncoupling of eNOS. This signaling cascade may represent a universal mechanism underlying eNOS dysfunction under pathophysiological conditions associated with oxidant stress.hydrogen peroxide ͉ tetrahydrobiopterin ͉ superoxide

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Section: Discussionmentioning

confidence: 97%

Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase

Chalupský

Cai

2005

Proc. Natl. Acad. Sci. U.S.A.

302

306

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“…Another possibility is that the NADPH activation occurs through endothelin receptors. A␤ upregulates endothelin-1 in cerebral blood vessels (Deane et al, 2003), and activation of endothelin receptors leads to production of ROS through NADPH oxidase (Duerrschmidt et al, 2000;Zheng et al, 2003). It is, therefore, conceivable that A␤ leads to activation of NADPH oxidase through endothelin receptors.…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Park¹,

Anrather²,

Zhou³

et al. 2005

J. Neurosci.

220

229

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Overproduction of the amyloid ␤ (A␤) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of A␤ on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by A␤. Thus, the free-radical production and the associated alterations in vasoregulation induced by A␤ are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91 phox ). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91 phox . The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91 phox -containing NADPH oxidase is the critical link between A␤ and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

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“…28 -30 Activation of vascular NAD(P)H oxidase and xanthine oxidase and endothelial nitric oxide synthase uncoupling 13,14,17,31,32 have been implicated in amplified ⅐O 2 Ϫ generation in experimental hypertension. Inhibition of ROS generation with apocynin (NAD(P)H oxidase inhibitor) or allopurinol (xanthine oxidase inhibitor) and radical scavenging with antioxidants or SOD mimetics decrease BP and prevent development of hypertension in most hypertensive models.…”

Section: Oxidative Stress In Experimental Hypertensionmentioning

confidence: 99%

Reactive Oxygen Species, Vascular Oxidative Stress, and Redox Signaling in Hypertension

2004

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Abstract-Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normalconditions the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase-derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies. Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. This article highlights current developments in the field of ROS and hypertension, focusing specifically on the role of oxidative stress in hypertension-associated vascular damage. In addition, recent clinical trials investigating cardiovascular benefits of antioxidants are discussed, and some explanations for the rather disappointing results from these studies are addressed. Finally, important avenues for future research in the field of ROS, oxidative stress, and redox signaling in hypertension are considered. Key Words: free radicals Ⅲ antioxidants Ⅲ resistance Ⅲ arteries Ⅲ hypertension, essential C ompelling experimental evidence indicates that reactive oxygen species (ROS) play an important pathophysiological role in the development of hypertension. This is due, in large part, to ⅐O 2 Ϫ excess (oxidative stress) and decreased NO bioavailability in the vasculature and kidneys and to ROS-mediated cardiovascular remodeling. [1][2][3] In human hypertension, biomarkers of systemic oxidative stress are elevated. 4 Treatment with superoxide dismutase (SOD) mimetics or antioxidants improves vascular and renal function, regresses vascular remodeling, and reduces blood pressure (BP). 5,6 Mouse models deficient in ROS-generating enzymes have lower BP compared with wild-type counterparts, and Angiotensin II (Ang II) infusion fails to induce hypertension in these mice. 7 Furthermore, experimental models with compromised antioxidant capacity develop hypertension. 8 In cultured vascular smooth muscle cells (VSMCs) and isolated arteries from hypertensive rats and humans, ROS production is enhanced, redox-dependent signaling is amplified, and antioxidant bioactivity is reduced. 9 Accordingly, evidence at multiple levels supports a role for ox...

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Gene Transfer of Human Guanosine 5′-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension

Cited by 126 publications

References 49 publications

Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase

Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Reactive Oxygen Species, Vascular Oxidative Stress, and Redox Signaling in Hypertension

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