An enzyme hydrolyzing methylated inhibitors of nitric oxide synthase is present in circulating human red blood cells

Kang, Ellen S.; Cates, Taylor; Harper, Dyette N.; Chiang, Thomas M.; Myers, Linda K.; Acchiardo, Sergio R.; Kimoto, Masumi

doi:10.1080/10715760100301211

Cited by 29 publications

(26 citation statements)

References 40 publications

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“…The serum concentrations of ADMA, an endogenous competitive inhibitor of NO synthesis, are elevated in hypercholesterolemia, even in the absence of overt atherosclerotic vascular disease 12) . This suggests that NOS inhibition by ADMA plays an important role early during atherosclerosis development, and elevated ADMA may be a potential marker of certain vascular diseases [22][23][24][25][26][27] . The higher serum ADMA concentrations were almost 2-fold higher in hypercholesterolemia 12,54) , as well as in hypertension 13,22) , coronary heart disease 23,24) , and diabetes mellitus 28) .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the reduction in NO bioavailability has been considered to be due partially to the action of a circulating competitive inhibitor of NOS, asymmetric dimethylarginine (ADMA) 12,13,[22][23][24][25] , which is endogenously produced in the process of protein arginine methylation 26,27) . There is a high prevalence of increased serum levels of ADMA in a number of cardiovascular disorders including hypercholesterolemia 9) , diabetes mellitus 28) , hypertension 13,22) , and coronary artery disease 23,24) .…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Pathway Activation and Impaired Red Blood Cell Deformability with Hypercholesterolemia

Kuwai

Hoshino

2006

JAT

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The pathophysiological effects of the activation or inhibition of the nitric oxide (NO)-mediated pathway on the deformability of red blood cells (RBC) were evaluated in the presence of hypercholesterolemia induced in rabbits fed a cholesterol-rich diet. RBC deformability was assessed using a microchannel array flow analyzer system. The maximum passage time (MPT) by flowing a suspension of RBC through the microchannels was used as an index of RBC deformability. During cholesterol feeding for 12 weeks, MPT gradually increased with no significant elevation in the serum asymmetric dimethylarginine (ADMA) and arginine/ADMA ratio. The reduction in RBC deformability associated with hypercholesterolemia was significantly improved during incubation with each of three different NO pathway activators: a NO donor, 8-bromo-cyclic GMP, and arginine; however, no additional reduction was observed with ADMA administration. The inhibition of NO synthase due to ADMA caused a significant reduction in the deformability of normal RBC, which was reversed with NO pathway activation. These results suggest that impaired RBC deformability may be associated with a dysfunction in the NO pathway that is partially dependent upon the accumulation of ADMA in RBC, and exogenous NO pathway activators may improve the microcirculation by restoring RBC deformability in the presence of hypercholesterolemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Pathway Activation and Impaired Red Blood Cell Deformability with Hypercholesterolemia

Kuwai

Hoshino

2006

JAT

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“…4 There is, to our knowledge, a single report in the literature that erythrocytes contain DDAH. 5 In our clinical study, we did not examine changes in blood pressure or cardiovascular function during estrogen therapy, whereas unfortunately Tsuda and co-workers did not measure erythrocyte DDAH activity in their study. Therefore, it is clear that only when these parameters are measured in the same study will we be in a position to comment fully on the various contributions of estrogen to ADMA/DDAH regulation and physiology in the cardiovascular system.…”

Section: Responsementioning

confidence: 95%

Estrogen and Asymmetric Dimethylarginine in Postmenopausal Women

Tsuda

Nishio

2004

Circulation

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We read with great interest the recent article by Holden et al 1 dealing with the relationship between estrogen and asymmetric dimethylarginine (ADMA) metabolism in postmenopausal women. The results of their study demonstrated that hormone replacement therapy significantly decreased plasma ADMA levels in postmenopausal women. In an in vitro study, Holden et al 1 observed that estrogen increased the activity of dimethylarginine dimethylaminohydrolase activity in endothelial cells. They proposed that estrogen can alter the catabolism and release of ADMA, which might partially contribute to the positive effect of estrogen on NO synthesis.Several studies have already reported that ADMA might have a crucial role in cardiovascular regulations. It was demonstrated that inhibition of NO bioavailability by ADMA and a subsequent reduction in endothelial function might contribute to the increase in blood pressure during salt intake in normotensive postmenopausal women not receiving estrogen. 2 Similarly, it was reported that there was a significant inverse correlation between plasma ADMA and flow-mediated dilatation of brachial artery, indicating that ADMA might be related to a decline in endothelial vasodilator function. 3 In a previous study, we showed that estrogen-induced improvement of membrane fluidity of erythrocytes was mediated by NO production, which was counteracted by ADMA in postmenopausal women. 4 The finding suggests that ADMA might actively participate in the regulation of cell membrane function in postmenopausal women. Because the deformability and microviscosity of erythrocyte membranes may be highly dependent on the membrane fluidity, the reduction in membrane fluidity could cause a disturbance in the blood rheological behavior and in the microcirculation, which might contribute to the pathophysiology of hypertension.Recently, Achan et al 5 demonstrated that intravenous infusion of ADMA increased blood pressure and systemic vascular resistance and decreased heart rate and cardiac output in humans. Therefore, we would like to know whether the hormone replacement therapy-induced decrease in plasma ADMA level might be accompanied by the changes in blood pressure and cardiac function. It would be important to assess more precisely whether ADMA may be involved in the cardiovascular disorders in postmenopausal women. ResponseWe thank Drs Tsuda and Nishio for their interest in our paper on estradiol effects on dimethylarginine dimethylaminohydrolase (DDAH) activity and the metabolism of asymmetric dimethylarginine (ADMA). 1 We previously showed a correlation between serum ADMA concentrations and blood pressure in pregnancy, 2 a state associated with high concentrations of circulating estrogens. In the present study, we examined whether estrogen had a direct role in the regulation of ADMA metabolism. Our results both from cell culture and from women using estrogen replacement therapy demonstrated the effect of estradiol on ADMA physiology. Some of these results have been independently confirmed. 3 We were intri...

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“…Dolayısıyla ADMA konsantrasyonunun başlıca düzenleyicisi DDAH enzimidir. Bugüne kadar DDAH enzimi varlığı ve aktivitesi karaciğer, böbrek, kalp ve iskelet kası, pankreas, plasenta, akciğer ve beyin dokularında, eritrosit, monosit ve polimorfonükleer lö-kositlerde gösterilmiştir [8,15,16]. DDAH enzimi sitozolik bir enzimdir.…”

Section: Adma'nın Yıkılmasıunclassified

Metabolism of asymmetric dimethylarginine and its clinical significance

Erbil¹,

Kurt²,

Yaman³

et al. 2012

Turk J Bioch

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ÖZETAsimetrik dimetilarjinin nitrik oksit sentaz enziminin endojen inhibitörüdür. Nitrik oksit endotel bağımlı vazodilatasyon, damar duvarındaki düz kas proliferasyonu, hücre-hücre etkileşimleri, platelet adezyon ve agregasyonunun inhibisyonu ile monosit adezyonu inhibisyonu gibi düzenleyici fonksiyonlara sahiptir. Arjinin amino asitinin modifiye bir formu olan asimetrik dimetilarjinin, metilenmiş proteinlerin proteolizi sonucu oluşur. Hücrede oluşan ve salınan net asimetrik dimetilarjinin miktarı, arjinin metilasyonu, metillenmiş arjinin içeren proteinlerin yıkımı, dimetilarjinin dimetilaminohidrolaz enzimi ile metabolizasyonu ve hücreden atılımı oranları arasındaki dengeye bağlıdır. Hücre içinde oluşan asimetrik dimetilarjininin neredeyse tamamı dimetilarjinin dimetilaminohidrolaz enzimi tarafından yıkılırken küçük miktardaki asimetrik dimetilarjinin, katyonik amino asit taşıyıcıları tarafından hücreden kan dolaşımına taşınır. Plazmaya geçen asimetrik dimetilarjinin ya böbreklerden değişime uğramadan idrar ile atılmakta ya da başlıca karaciğer ve böbrekte olmak üzere tekrar hücre içine alınarak dimetilarjinin dimetilaminohidrolaz enzimi tarafından metabolize edilmektedir. Plazma asimetrik dimetilarjinin seviyesi, çeşitli avantaj ve dezavantajları bulunması ile birlikte, yüksek performanslı sıvı kromatografisi, kütle spektrometresi ve ELISA ile ölçülebilir. Plazmadaki asimetrik dimetilarjininin biyolojik olarak aktif olup olmadığı kesin olarak bilinmemektedir. Ancak literatürde pek çok klinik durumda plazma asimetrik dimetilarjinin konsantrasyonunun yüksek olduğunu gösteren çalışmalar mevcuttur. Bölümümüzde yapılan klinik ve deneysel çalışmalarda da literatürle uyumlu olarak kronik böbrek hastalığı, hipertansiyon, endometriosis ve şizofreni hastalarında yüksek olarak bulunmuştur. Özellikle, nitrik oksit gibi, kardiyovasküler sistem üzerine birçok düzenleyici etkisi bulunan bir molekülün sentezini inhibe etmesi nedeni ile günümüzde yeni bir kardiyovasküler risk faktörü olarak değerlendirilmektedir. Endotel disfonksiyonuna yol açması ve endotel disfonksiyonun birçok hastalığın patogenezinde önemli olması, yakın gelecekte de asimetrik dimetilarjinin üzerine araştırmaların devam edeceğine işaret etmektedir. Anahtar Sözcükler: Asimetrik dimetilarjininin, nitrik oksit, dimetilarjinin dimetilaminohidrolaz, endotel disfonksiyonu Çıkar çatışması: Yazarların çıkar çatışması bulunmamaktadır. ABSTRACTAsymmetric dimethylarginine is an endogenous inhibitory of nitric oxide synthase enzyme. Nitric oxide has regulatory functions such as endothelial dependent vasodilatation, smooth muscle proliferation in vessel wall, cell-cell interactions, platelet aggregation and adhesion inhibition and monosit adhesion inhibition. Asymmetric dimethylarginine, a modified form of arginine amino acid, is produced by proteolysis of methylated proteins. Net amount of produced and released ADMA depends on the balance between arginine methylation, degradation of proteins containing methylated arginine and metabolism by the enzyme dimetilarjinin di...

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An enzyme hydrolyzing methylated inhibitors of nitric oxide synthase is present in circulating human red blood cells

Cited by 29 publications

References 40 publications

Nitric Oxide Pathway Activation and Impaired Red Blood Cell Deformability with Hypercholesterolemia

Nitric Oxide Pathway Activation and Impaired Red Blood Cell Deformability with Hypercholesterolemia

Estrogen and Asymmetric Dimethylarginine in Postmenopausal Women

Metabolism of asymmetric dimethylarginine and its clinical significance

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