Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase.
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Arginine↗
Biomedical subjects
Patrick Vallance
Publications and source records attributed to Patrick Vallance.
The DDAH/ADMA/NOS pathway.
An increasing number of reports in the literature indicate that endogenously produced inhibitors of nitric oxide synthase (NOS), particularly asymmetric dimethylarginine (ADMA) regulate nitric oxide generation in numerous disease states. Two dimethylarginine dimethylaminohydrolase (DDAH) enzymes metabolise ADMA. We and others have postulated that activity of DDAH is a key determinant of ADMA levels in vivo. This review summarises recent advances in the regulation and function of DDAH enzymes and its role in the regulation of nitric oxide generation.
Amidohydrolases↗
Nitric oxide: therapeutic opportunities.
Fifteen years after the discovery of nitric oxide as a biological mediator how close are new therapies? This article describes the roles of nitric oxide, illustrates how its discovery is altering the way in which certain established drugs are being used and reviews new therapeutic developments.
Animals↗
Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse.
Conventional cardiovascular risk factors such as cholesterol and blood pressure do not account fully for variation in coronary heart disease suggesting the involvement of additional mechanisms. We have examined the effects of a chronic psychological stress protocol on the development of atherosclerosis in the apolipoprotein E knockout mouse. We observed a 3-fold increase in staining for atheroma accompanied by a 10-fold increase in corticosterone concentrations in mice stressed for 12 weeks. These data suggest that chronic mild stress can induce or accelerate the development of atherosclerosis.
Animals↗
S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase.
The enzyme dimethylarginine dimethylaminohydrolase (DDAH) hydrolyses asymmetrically methylated arginine residues that are endogenously produced inhibitors of nitric oxide synthases (NOS). We and others have proposed that DDAH activity is a key determinant of intracellular methylarginine concentrations and that factors that regulate the activity of DDAH may modulate nitric oxide (NO) production in vivo. We recently solved the crystal structure of a bacterial DDAH and identified a Cys-His-Glu catalytic triad [Murray-Rust, J., Leiper, J. M., McAlister, M., Phelan, J., Tilley, S., Santa Maria, J., Vallance, P. & McDonald, N. (2001) Nat. Struct. Biol. 8, 679-683]. The presence of a reactive cysteine residue (Cys-249) in the active site of DDAH raised the possibility that DDAH activity might be directly regulated by S-nitrosylation of this residue by NO. In the present study, we demonstrate that recombinant DDAH is reversibly inhibited after incubation with NO donors in vitro. Similarly mammalian DDAH in cytosolic extracts is also reversibly inhibited by NO donors. In cultured endothelial cells, heterologously expressed human DDAH II was S-nitrosylated after cytokine induced expression of the inducible NOS isoforms. The implication of these findings is that under certain conditions when NO generation increases, S-nitrosylation diminishes DDAH activity and this would be expected to lead to accumulation of asymmetric dimethylarginine and inhibition of NOS. This observation may help explain why expression of iNOS often leads to inhibition of activity of constitutively expressed NOS isozymes. We also identify Cys-His-Glu as a nitrosylation motif that is conserved in a family of arginine handling enzymes.
Amidohydrolases↗
Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin.
BACKGROUND: Inflammation and infection may initiate and promote atherosclerosis or its complications by adverse effects on the vascular endothelium. The mechanisms by which aspirin reduces cardiovascular risk might involve anti-inflammatory actions or direct effects on the endothelium in addition to its antiplatelet action. We investigated the role of aspirin in modulating endothelial dysfunction induced by an experimental inflammatory stimulus. METHODS AND RESULTS: An inflammatory response was generated in healthy volunteers by Salmonella typhi vaccination. Venous occlusion plethysmography was used to assess resistance vessel responses (16 hours before and 8 hours after vaccination) to the endothelium-dependent dilator bradykinin (BK) and the endothelium-independent dilator glyceryl-trinitrate (GTN). Twelve subjects were randomized to receive either aspirin 1.2 g orally or placebo 2 hours before vaccination. After vaccination alone there was suppression of the response to BK in the placebo group (P=0.01), with no change in response to GTN. In the aspirin group there was no change in the response to either BK or GTN after vaccination. Aspirin treatment prevented vaccine-induced elevation of interleukin-1 receptor antagonist but enhanced the generation of tumor necrosis factor-alpha compared with placebo. In an additional 5 individuals, local intrabrachial aspirin (10 mg/min for 15 minutes) failed to restore responses to BK after vaccination. CONCLUSIONS: Experimental inflammation produces endothelial dysfunction, which can be prevented by pretreatment with aspirin. Locally administered aspirin does not reverse vaccine-induced endothelial dysfunction once established. The protective effects of aspirin on inflammation-induced endothelial dysfunction may be through modulation of the cytokine cascade.
Administration, Oral↗
Enhanced atherogenesis is not an obligatory response to systemic herpesvirus infection in the apoE-deficient mouse: comparison of murine gamma-herpesvirus-68 and herpes simplex virus-1.
Viral and bacterial infectious agents have been implicated in the etiology of atherosclerosis. We have previously shown that a gamma-herpesvirus can accelerate atherosclerosis in the apolipoprotein E-deficient (apoE-/-) mouse. To address whether a virally induced systemic immune response is sufficient to trigger enhanced atheroma formation, we infected apoE-/- mice with murine gamma-herpesvirus-68 (MHV-68) or herpes simplex virus-1 (HSV-1). In this study, we show that both viruses were able to induce a cell-mediated and humoral immune response in the apoE-/- mouse, which was sustained over a period of 24 weeks. Although intranasal or intraperitoneal infection with MHV-68 induced similar levels of virus-specific IgG1 and IgG2a antibodies in the serum of apoE-/- mice, those infected with HSV-1 showed higher anti-HSV-1 IgG2a compared with IgG1 antibody levels. In addition, viral message was not detected in the aortas of HSV-1-infected animals, whereas we have shown previously that MHV-68 mRNA can be detected in the aortas of infected mice as early as 5 days after infection. Compared with control mice, apoE-/- mice infected with MHV-68 showed accelerated atherosclerosis, whereas mice infected with HSV-1 did not. These data indicate that a systemic immune response to any particular infectious agent is insufficient to induce enhanced atherosclerosis in the apoE-/- mouse and point to specific infections or immune mechanisms that might be essential for virally enhanced atherogenesis.
Animals↗
all-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase.
all-trans-Retinoic acid (atRA) has important effects on the developing and mature cardiovascular system. Nitric oxide (NO) production has been associated with the atRA-induced differentiation of neuronal cells, and we hypothesized that NO may also mediate certain actions of atRA in the cardiovascular system. We studied the effects of atRA on NO production by endothelial cells and determined whether regulation of enzymes responsible for metabolism of asymmetric dimethylarginine (ADMA) contributed to the effects seen. Murine endothelioma (sEnd.1) cells were incubated with or without atRA. Nitrite production was determined using the Griess reaction. The expression of NO synthase (NOS) and dimethylarginine dimethylaminohydrolase (DDAH) genes was determined by Northern blotting. A reporter gene assay was also used to study the effect of atRA on the DDAH II promoter. atRA significantly increased nitrite production by sEnd.1 cells despite no increase in eNOS expression. atRA also increased DDAH II gene expression and promoter activity and reduced the ratio of ADMA to symmetric dimethylarginine (SDMA) in culture medium. The DDAH inhibitor 4124W significantly reduced the induction of NO synthesis by atRA. The present study demonstrates that atRA increases NO synthesis in endothelial cells without increasing eNOS expression. atRA also increases the expression of DDAH II, the predominant DDAH isoform in endothelial cells. Our data suggests that the induction of NO synthesis by atRA may be facilitated by DDAH II. This pathway may help to explain some of the effects of atRA on the cardiovascular system.
Amidohydrolases↗
Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.
Brachial Artery↗
Blocking NO synthesis: how, where and why?
Nitric oxide (NO) is a key physiological mediator, and the association of disordered NO generation with many pathological conditions has led to much interest in pharmacologically modulating NO levels. However, the wide range of processes in which NO has been implicated, and the fact that increases or decreases in NO levels might be therapeutically desirable depending on the condition or even at different stages of the same condition, pose considerable challenges for drug development. Here, we focus on the rationale and potential for approaches that reduce NO synthesis, which have led to the development of several compounds that will shortly be entering clinical trials.
Animals↗
The effects of hormone replacement therapy on endothelial function in women with Turner's syndrome.
OBJECTIVES: To examine the effect of hormone replacement therapy (HRT) on endothelial function of forearm resistance vessels in women with Turner's syndrome. DESIGN: Subjects were studied on three occasions: on their usual HRT (study 1), then after 6 weeks off HRT (study 2) and finally after a further 6 weeks on HRT (study 3). PATIENTS: Seven young women with Turner's syndrome were studied. MEASUREMENTS: Forearm blood flow in response to intrabrachial infusion of bradykinin, 10, 30, 100 pmol/min (endothelium-dependent vasodilator), glyceryl trinitrate, 4, 8, 16 nmol/min (GTN; endothelium-independent vasodilator), noradrenaline, 60, 120, 240 pmol/min (NA, alpha-adrenergic receptor agonist) and NG-monomethyl-l-arginine, 1, 2, 4 micromol/min (L-NMMA; NO synthase inhibitor) was assessed by bilateral venous plethysmography. RESULTS: The vasodilator response to bradykinin, expressed as the within-subject mean difference in area under the dose-response curve between study 2 and study 1, was significantly diminished (-744.2 +/- 287.2, P = 0.04) but improved 6 weeks after HRT recommencement. However, there was no significant change in response to GTN (between study 2 and study 1, 189.5 +/- 247.8, P = 0.47). The vasoconstrictor response to L-NMMA was also diminished in study 2 when compared to study 1 (-100.4 +/- 35.4, P = 0.039) and was restored after HRT was recommenced (between study 3 and study 2, 117.5 +/- 69.3, P = 0.17) whereas there was no significant difference in response to NA between study 2 and study 1 (76.7 +/- 50.6, P = 0.18) or study 3 and study 2 (-70.8 +/- 71.1, P = 0.38). CONCLUSIONS: HRT improves endothelial function in women with Turner's syndrome.
Adult↗
Animal experiments and the doctor.
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Animal Use Alternatives↗
Developing an open relationship with the drug industry.
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Drug Costs↗