Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang, Yixuan; Janssens, Stefan; Wingler, Kirstin; Schmidt, Harald; Moens, An L.

doi:10.1152/ajpheart.01315.2010

Cited by 78 publications

(55 citation statements)

References 163 publications

(185 reference statements)

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“…A number of lifestyle changes and medical interventions that enhance NO bioavailability also improve insulin sensitivity and cardiometabolic risk and are highly effective treatments for cardiovascular disease [46]. …”

Section: No-directed Therapymentioning

confidence: 99%

Characterization of the Role of Nitric Oxide and Its Clinical Applications

Levine¹,

Punihaole

Levine³

2012

Cardiology

221

165

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Nitric oxide (NO) has long been known as endothelium-derived relaxing factor. It is a vasodilator, modulating vascular tone, blood pressure and hemodynamics, a role exploited by nitrate donor therapy for angina, heart failure, pulmonary hypertension and erectile dysfunction. In addition, its powerful antioxidant, anti-inflammatory and antithrombotic actions are antiatherogenic with antiatherothrombotic impact. NO signaling modulates skeletal muscle and myocardial contractility and metabolism and is intimately linked with insulin signaling. Vascular and muscle NO signaling coordinate skeletal muscle and myocardial energy demand with supply and are critical for both carbohydrate and fatty acid total-body homeostasis. NO signaling in mitochondria underlies much of NO’s metabolic effect, which, at low physiologic levels, links cellular energy demand with mitochondrial energy supply, while beneficially affecting mitochondrial oxidative stress and calcium handling. Mitochondria are also the site for the life-threatening deleterious effects arising from inflammation-related excessive NO levels. NO-deficient states are characterized by cell senescence, oxidative stress, inflammation, endothelial dysfunction, vascular disease, insulin resistance and type 2 diabetes mellitus. NO-enriching therapy would be expected to be of benefit not only for its hemodynamic but also for its metabolic impact. In contrast, strategies are needed to curtail excessive NO in states such as septic shock.

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Section: No-directed Therapymentioning

confidence: 99%

Characterization of the Role of Nitric Oxide and Its Clinical Applications

Levine¹,

Punihaole

Levine³

2012

Cardiology

221

165

View full text Add to dashboard Cite

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“…The review was focused on general aspects without regard for advanced research aspects. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental, and clinical, experiences working on vasoplegic endothelium dysfunction [1][2][3][4][5][6][7][8][9][10][11][12].…”

Section: Merits Citing Dr Salvador Moncada (Paul Dudley Whitementioning

confidence: 99%

Cardiovascular Therapeutics Targets on the NO–sGC–cGMP Signaling Pathway: A Critical Overview

Évora

Évora²,

Celotto³

et al. 2012

CDT

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In a brief overview, in NO-sGC-cGMP signaling in a blood vessel, l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Heme-dependent sGC stimulators and hem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. Studies of the 90's definitively established the role of endothelium in all cardiovascular diseases, which were associated with endothelial dysfunction by impaired release of endothelium-derived relaxing factors with consequent risk of spasm and thrombosis. The rationale of this review is based on the fact that the discovery of NO changed the concepts of cardiovascular disease mechanisms. However, considering the jargon "from the bench to clinical practice" we concluded that a potential therapeutic revolution did not follow the pathophysiological revolution. The review is focused on general aspects without regard for advanced research aspects, and designed in two main groups: the NO/cGMP positive stimulators and blockers as "future and encouraging" new therapeutic drugs. The potential vasodilators include 1) NOS uncoupling; 2) NOS enhancers (AVE compounds); 3) NO donors (nitrovasodilators); 4) NO-independent activators (BAY compounds), and; 5) PDE5 inhibitors. The potential vasoconstrictors include 1) NOS-blockers (L-NAME, L-NMMA); 2) sGC-blockers (methylene blue), and; 3) PDEs. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental and clinical experience working on vasoplegic endothelium dysfunction.

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“…The detection of a progesteronebinding moiety on the plasma membranes of human aorta endothelial cells and on human umbilical vein endothelial cells (HUVECs) (63,69) is consistent with such a mechanism of action mediated through a membrane progesterone receptor. Nitric oxide, which is synthesized in vascular endothelial cells by the enzyme endothelial nitric oxide (NO) synthase (eNOS), is a principal regulator of vasodilation through its action on vascular smooth muscle cells, causing their relaxation (17,41,73). Studies in animal models suggest that nanomolar concentrations of progesterone induce rapid vasodilation of aorta and arteries through this mechanism (52,53).…”

mentioning

confidence: 99%

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Pang

Dong

Thomas

2015

American Journal of Physiology-Endocrinology and Metabolism

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Pang Y, Dong J, Thomas P. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-␣. Am J Physiol Endocrinol Metab 308: E899 -E911, 2015. First published March 24, 2015; doi:10.1152/ajpendo.00527.2014.-Progesterone exerts beneficial effects on the human cardiovascular system by inducing rapid increases in nitric oxide (NO) production in vascular endothelial cells, but the receptors mediating these nongenomic progesterone actions remain unclear. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that progesterone binds to plasma membranes of HUVECs with the characteristics of membrane progesterone receptors (mPRs). The selective mPR agonist Org OD 02-0 had high binding affinity for the progesterone receptor on HUVEC membranes, whereas nuclear PR (nPR) agonists R5020 and medroxyprogesterone acetate displayed low binding affinities. Immunocytochemical and Western blot analyses confirmed that mPRs are expressed in HUVECs and are localized on their plasma membranes. NO levels increased rapidly after treatment with 20 nM progesterone, Org OD 02-0, and a progesterone-BSA conjugate but not with R5020, suggesting that this progesterone action is at the cell surface and initiated through mPRs. Progesterone and Org OD 02-0 (20 nM) also significantly increased endothelial nitric oxide synthase (eNOS) activity and eNOS phosphorylation. Knockdown of mPR␣ expression by treatment with small-interfering RNA (siRNA) blocked the stimulatory effects of 20 nM progesterone on NO production and eNOS phosphorylation, whereas knockdown of nPR was ineffective. Treatment with PI3K/ Akt and MAP kinase inhibitors blocked the stimulatory effects of progesterone, Org OD 02-0, and progesterone-BSA on NO production and eNOS phosphorylation and also prevented progesterone-and Org OD 02-0-induced increases in Akt and ERK phosphorylation. The results suggest that progesterone stimulation of NO production in HUVECs is mediated by mPR␣ and involves signaling through PI3K/Akt and MAP kinase pathways. membrane progesterone receptors; human vascular endothelial cells; rapid progesterone action; nitric oxide; nitric oxide synthase FEMALE REPRODUCTIVE HORMONES are widely considered to have beneficial effects on cardiovascular functions in women. The lower incidence of cardiovascular disease in middle-aged premenopausal women than in men and postmenopausal women has been attributed to the presence of female sex steroids in the circulation (22,27,41,47). Blood pressure is typically lower in women than in men and often drops during pregnancy when circulating levels of estrogens and progesterone are elevated (30,70,71). Furthermore, synthesis of a major regulator of vasodilation, nitric oxide (NO), is greater in women than in men (14). These sex differences in the occurrence of cardiovascular disease are due partly to the well-known beneficial effects of estrogens, which include upregulation of NO production in human endothelial cells (7,18,28,33). Numerous...

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Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Cited by 78 publications

References 163 publications

Characterization of the Role of Nitric Oxide and Its Clinical Applications

Characterization of the Role of Nitric Oxide and Its Clinical Applications

Cardiovascular Therapeutics Targets on the NO–sGC–cGMP Signaling Pathway: A Critical Overview

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

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