The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) predicts LV mass independent of afterload

Sverdlov, Aaron L.; Ngo, D.; Nightingale, Angus K; Rajendran, S; Mishra, Kumaril; Heresztyn, Tamila; Ritchie, Rebecca H; Marwick, Thomas H.; Frenneaux, Michael; Horowitz, John D.

doi:10.1016/j.niox.2011.04.009

Cited by 14 publications

(13 citation statements)

References 39 publications

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“…Traditional nitrovasodilators increase NO˙levels but are at risk of tolerance development (16,17,44); conversely statins and ACE inhibitors enhance NOS activity (1,50,61), but concomitant increases in ADMA may also limit their NO˙-elevating ability (57). Our findings now indicate that HNO donors represent a direct means of stimulating sGC, bypassing the potential roadblocks of nitrate tolerance, ADMA and possibly also sGC oxidation state, and may thus emerge as a legitimate antihypertrophic therapy over and above ACE inhibition.…”

Section: Discussionmentioning

confidence: 70%

“…Cardiomyocyte hypertrophy was measured as 2D area of individual cells (m 2 , 50 cells/treatment group, 1,034 ϫ 1,300 resolution, ϫ10 magnification) at completion of 48-h drug treatment, as described previously (28,31). Changes in cardiomyocyte hypertrophic gene expression induced by 48-h treatment with ET 1, in the presence and absence of IPA-NO or DEA-NO, was also determined, at the level of the fetal genes, atrial, and B-type natriuretic peptides (ANP and BNP), via real time PCR, as previously described (1,57). Real-time PCR reagents were all of molecular biology grade and included Taqman reverse transcription reagents, Taqman Sybr Green PCR master mix, DNase treatment kits (Applied Biosystems, Scoresby, Australia), as well as forward and reverse primers for real-time PCR (Geneworks, Thebarton, Australia).…”

Section: This Investigation Conforms To Both Thementioning

confidence: 99%

“…NO˙is, however, yet to be realized as a pharmacotherapy for cardiac hypertrophy, largely a consequence of limitations at the level of myocardial asymmetric dimethylarginine (ADMA) and NO synthase (NOS; Ref. 57). HNO, a redox sibling of NO˙, is a novel regulator of cardiovascular function (26,38).…”

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confidence: 99%

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HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO˙

Irvine

Cao

Gossain

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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RH. HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO˙. Am J Physiol Heart Circ Physiol 305: H365-H377, 2013. First published May 31, 2013 doi:10.1152/ajpheart.00495.2012 is a redox congener of NO˙. We now directly compare the antihypertrophic efficacy of HNO and NO˙donors in neonatal rat cardiomyocytes and compare their contributing mechanisms of actions in this setting. Isopropylamine-NONOate (IPA-NO) elicited concentrationdependent inhibition of endothelin-1 (ET1)-induced increases in cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic IPA-NO actions were significantly attenuated by L-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (cGMP-dependent protein kinase inhibitor), and 1-H-(1,2,4)-oxodiazolo-quinxaline-1-one [ODQ; to target soluble guanylyl cyclase (sGC)] but were unaffected by carboxy-PTIO (NO˙scavenger) or CGRP8-37 (calcitonin gene-related peptide antagonist). Furthermore, IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an L-cysteine-sensitive effect) and stimulated sGC activity threefold, without detectable NO˙release. IPA-NO also suppressed ET1-induced cardiomyocyte superoxide generation. The pure NO˙donor diethylamine-NONOate (DEA-NO) reproduced these IPA-NO actions but was sensitive to carboxy-PTIO rather than L-cysteine. Although IPA-NO stimulation of purified sGC was preserved under pyrogallol oxidant stress (in direct contrast to DEA-NO), cardiomyocyte sGC activity after either donor was attenuated by this stress. Excitingly IPA-NO also exhibited acute antihypertrophic actions in response to pressure overload in the intact heart. Together these data strongly suggest that IPA-NO protection against cardiomyocyte hypertrophy is independent of both NO˙and CGRP but rather utilizes novel HNO activation of cGMP signaling. Thus HNO acutely limits hypertrophy independently of NO˙, even under conditions of elevated superoxide. Development of longer-acting HNO donors may thus represent an attractive new strategy for the treatment of cardiac hypertrophy, as stand-alone and/or add-on therapy to standard care. cardiac hypertrophy; cGMP-dependent protein kinase; nitric oxide; nitroxyl; superoxide CURRENT PHARMACOTHERAPY FOR heart failure tends to delay, but not reverse, cardiac hypertrophy. We have previously shown that NOṡ ignaling is an important antihypertrophic mechanism in the heart (44). NO˙is, however, yet to be realized as a pharmacotherapy for cardiac hypertrophy, largely a consequence of limitations at the level of myocardial asymmetric dimethylarginine (ADMA) and NO synthase (NOS; Ref. 57). HNO, a redox sibling of NO˙, is a novel regulator of cardiovascular function (26,38). NO˙and HNO share several common cardiac and vascular protective actions, ranging from potent vasodilator (2, 10, 12-14, 22, 23, 59) and antiplatelet actions (3, 4) to, more recently, antihypertrophic actions in cardiomyocytes (31). These actions are all mediated predominantly via sGC (10...

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Section: Discussionmentioning

confidence: 70%

Section: This Investigation Conforms To Both Thementioning

confidence: 99%

See 1 more Smart Citation

HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO˙

Irvine

Cao

Gossain

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Notably, NO and its main antagonist, ADMA, have opposite effects on the heart. Indeed NO restrains myocardial growth [8] while ADMA, by removing this restraint, promotes left ventricular hypertrophy (LVH) [9,10]. Of note ADMA interferes with a fundamental biological function like the regulation of the enzyme telomerase [11], the enzyme that regulates the length of cell telomeres, i.e.…”

Section: Systems Physiology: Basic Concepts and Inter-organ Cross-talkmentioning

confidence: 99%

Chronic Kidney Disease (CKD) as a Systemic Disease: Whole Body Autoregulation and Inter-Organ Cross-Talk

Zoccali

Tripepi

Dounousi

et al. 2014

Kidney Blood Press Res

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The inter-organ cross-talk and the functional integration of organ systems is an exceedingly complex process which until now has been investigated with a reductionist approach. CKD perturbs the inter-organ cross-talk and demands central resetting of autonomic (nervous) control of organ systems. Due to limitations inherent to the reductionist approach, we currently identify CKD-related pseudo-syndromes and largely fail at describing the complex systemic inter-relationships set into motion by renal damage and renal dysfunction. A mature technology for a system-analysis approach to physiology and pathophysiology of CKD now exists. System biology will allow in depth understanding of complex diseases like CKD and will set the stage for predictive, preventive and personalized medicine, a long-standing dream of doctors and patients alike.

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“…18 Previous investigation has suggested that plasma ADMA concentration may be correlated with age-associated changes in left ventricular (LV) mass in a normal, untreated, ageing population. 19 To date, there is only one report of the relationship between ADMA levels and echocardiographic parameters, and the authors only used one methodology, M-mode echocardiography. 20 In this study, we aimed to evaluate circulating ADMA levels according to diabetes duration and to determine the relationship between ADMA levels and subclinical atherosclerosis assessed by CIMT and cardiac muscle function evaluated by ultrasonographic Doppler tissue imaging in children and adolescents with T1DM.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric dimethylarginine levels and diabetes duration: Relationship with measures of subclinical atherosclerosis and cardiac function in children and adolescents with Type 1 diabetes

Ersoy

Eroğlu

Çetin

et al. 2018

Diabetes and Vascular Disease Research

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Aims: We aimed to evaluate asymmetric dimethylarginine levels in young patients with Type 1 diabetes mellitus according to diabetes duration and to examine the relationship between these levels and measures of atherosclerosis and myocardial function. Materials and methods: In total, 83 patients (8.5-22 years) with Type 1 diabetes mellitus were stratified by diabetes duration: 12-60 months (Group 1, n = 27), >60-120 months (Group 2, n = 29) and >120 months (Group 3, n = 27). Asymmetric dimethylarginine levels were assessed. Carotid intima-media thickness was measured. Myocardial function was assessed by M-mode, conventional Doppler and tissue Doppler echocardiography. Results: Asymmetric dimethylarginine level was significantly higher in Group 1, while carotid intima-media thickness was significantly greater in Group 3 (p < 0.05). Tissue Doppler echocardiography showed the ratio of peak early to peak late diastolic myocardial annular velocity decreased significantly in Groups 2 and 3 with a negative correlation with duration (r: −0.310, p = 0.004) and HBA1c levels (r = −0.391, p < 0.001). Myocardial performance index in all groups and isovolumic relaxation time in Group 3 increased significantly. Asymmetric dimethylarginine levels were negatively correlated with carotid intima-media thickness and isovolumic relaxation time (p < 0.05). Conclusion: In contrast to adult diabetics, asymmetric dimethylarginine concentration decreases as diabetes duration increases in young Type 1 diabetic patients and is associated with worsening measures of cardiovascular risk and poorer diastolic function.

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The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) predicts LV mass independent of afterload

Cited by 14 publications

References 39 publications

HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO˙

HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO˙

Chronic Kidney Disease (CKD) as a Systemic Disease: Whole Body Autoregulation and Inter-Organ Cross-Talk

Asymmetric dimethylarginine levels and diabetes duration: Relationship with measures of subclinical atherosclerosis and cardiac function in children and adolescents with Type 1 diabetes

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