Abstract 258: Angiotensin 1-7 Attenuates Endothelin-1-Induced Endothelial Cell Inflammation and Growth Through Nitric Oxide Production and Activation of Mas and EndothelinB Receptors

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Hiba Yusuf ◽  
Augusto C Montezano ◽  
Glaucia E Callera ◽  
Aurille Nguyen Dinh Cat ◽  
Robson A Santos ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
No Production ◽  
Beneficial Effects ◽  
Mas Receptor ◽  
Mediated Effects ◽  
Endothelin System ◽  
Etb Receptor

In pulmonary hypertension, where the endothelin system plays a major role, the vasoprotective axis of the rennin angiotensin system (ACE2-Ang (1-7)-Mas) seems to be protective. However, the exact mechanisms are still elusive and whether Ang 1-7 counterbalancing effects are beyond interactions with Ang II system is unknown. In this study, we assessed whether Ang 1-7 influences/interacts with the ET-1 system in endothelial cells. Cultured human microvascular endothelial cells (HMEC) were studied. HMEC were stimulated with ET-1 (10-7 mol/L) in the absence and presence of Ang 1-7 (10-7 mol/L), BQ788 (an ETBR antagonist), BQ 123 (an ETAR antagonist) and A779 (Mas receptor inhibitor) (10-6 mol/L). Expression of pro-inflammatory mediator (VCAM-1), cell growth marker (PCNA), Mas, ETBR expression and eNOS activation was determined by immunoblotting. ET-1 significantly increased expression of VCAM-1 (138.90% vs control, p<0.05) and PCNA (125% vs control, p<0.05). Ang 1-7 alone did not modulate pro-inflammatory and growth mediators, but significantly inhibited the effects of ET-1 on VCAM-1 (95.55%) and PCNA (103.83%) expression, an effect mediated by Mas receptor activation (after A779: VCAM-1: 226.15%; PCNA: 120% vs control, p<0.05). Ang 1-7 increased NO production (Ctl: 7.5 vs Ang 1-7: 20 RFU/ug of protein, by microfluorescence). Inhibition of Ang 1-7-induced NO production by L-NAME, inhibited Ang 1-7-mediated effects on ET-1-induced VCAM-1 (160%) and PCNA (125%), p<0.05. Ang 1-7 significantly increased expression of ETB receptors (175.63% vs control, p<0.05), an effect attenuated by A779. Ang 1-7 (166.94% vs control, p<0.05) and ET-1 (146.04% vs control, p<0.05) increased eNOS phosphorylation in HMEC. Blockade of Mas and ETB receptor inhibited Ang 1-7 and ET-1 effects on eNOS activation. BQ123, but not BQ788, blocked ET-1-stimulated inflammation/growth in HMEC (VCAM-1: 75%, PCNA: 100%, p<0.05). In conclusion, Ang 1-7 negatively modulates proinflammatory and mitogenic actions of ET-1, through crosstalk between Mas and ETB receptors, and increase in NO production. These data highlight some molecular mechanisms whereby Ang 1-7 may exert beneficial effects in pulmonary hypertension and suggests a novel mechanism for Ang 1-7 signalling in HMEC.

Abstract 1746: Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) Mediates Vascular Repair By HDL Receptor Activation And Sphingosine Kinase (SK-1)/Sphingosine 1-Phosphate (S1P) Dependent Nitric Oxide (NO) Generation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sergio Li Calzi ◽  
Jennifer L Kielczewski ◽  
Evan McFarland ◽  
Kyung Hee Chang ◽  
Aqeela Afzal ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Scavenger Receptor ◽  
Receptor Activation ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
Sphingosine 1 Phosphate ◽  
Active Motor ◽  
Umbilical Vein Endothelial Cells ◽  
Igfbp 3

Purpose: We demonstrated that IGFBP-3 stimulates hematopoietic stem cells (HSC) to differentiate into endothelial cells, form capillaries, and stabilize the vasculature (Chang, et al, PNAS 2007). Local IGFBP- 3 production is increased by hypoxia and facilitates the homing of HSC to areas of injury. In the circulation, IGFBP-3 is bound to HDL. In this study, we investigated the signaling pathways responsible for the robust migratory effects of IGFBP-3. Methods: The effects of IGFBP-3 on NO generation in human vascular precursors (CD 34 + , CD14 − ), human lung microvascular endothelial cells, and human umbilical vein endothelial cells were examined using DAF-FM fluorescence. Western analysis was use for detection of eNOS and vasodilator-stimulated phosphoprotein (VASP), which redistributes to lamellipodia forming an active motor complex that supports motility and is phosphorylated in response to NO. Localization of VASP was performed by immunohistochemistry. SK-1 was assessed following IGFBP-3 stimulation. Results: In CD34 + cells and endothelial cells, IGFBP-3 stimulated eNOS phosphorylation at Ser1177 (102 ± 1.8%, P = 0.0002) and increased NO generation (275 ± 50%, P = 0.05) by increasing SK-1 and S1P generation. IGFBP-3 was bound and internalized by the HDL receptor, scavenger receptor 1B (SR1B). NO generation following IGFBP-3 exposure was reduced by SK inhibitors or SR-1B blocking antibody pretreatment (35 ± 5%, P < 0.02). IGFBP-3 generated NO increased phosphorylation of VASP at Ser239 and promoted the redistribution of VASP to lamellipodia. Conclusions: IGFBP-3 effects on cell migration are NO dependent and mediated in part by activation of the HDL receptor SR1B suggesting that some of the beneficial effects of HDL are mediated by the association of IGFBP-3.

scholarly journals Cilostazol Induces eNOS and TM Expression via Activation with Sirtuin 1/Krüppel-like Factor 2 Pathway in Endothelial Cells

2021 ◽  
Vol 22 (19) ◽  
pp. 10287
Author(s):  
Chih-Hsien Wu ◽  
Yi-Lin Chiu ◽  
Chung-Yueh Hsieh ◽  
Guo-Shiang Tsung ◽  
Lian-Shan Wu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Nitric Oxide Synthase ◽  
Umbilical Vein ◽  
Sirtuin 1 ◽  
No Production ◽  
Beneficial Effects ◽  
Umbilical Vein Endothelial Cells ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cilostazol was suggested to be beneficial to retard in-stent atherosclerosis and prevent stent thrombosis. However, the mechanisms responsible for the beneficial effects of cilostazol are not fully understood. In this study, we attempted to verify the mechanism of the antithrombotic effect of cilostazol. Human umbilical vein endothelial cells (HUVECs) were cultured with various concentrations of cilostazol to verify its impact on endothelial cells. KLF2, silent information regulator transcript-1 (SIRT1), endothelial nitric oxide synthase (eNOS), and endothelial thrombomodulin (TM) expression levels were examined. We found cilostazol significantly activated KLF2 expression and KLF2-related endothelial function, including eNOS activation, Nitric oxide (NO) production, and TM secretion. The activation was regulated by SIRT1, which was also stimulated by cilostazol. These findings suggest that cilostazol may be capable of an antithrombotic and vasculoprotective effect in endothelial cells.

Punicalagin Prevents Hypoxic Pulmonary Hypertension via Anti-Oxidant Effects in Rats

2016 ◽  
Vol 44 (04) ◽  
pp. 785-801 ◽  
Author(s):  
Jingyun Shao ◽  
Peng Wang ◽  
An Liu ◽  
Xusheng Du ◽  
Jie Bai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Pulmonary Arteries ◽  
Pomegranate Juice ◽  
No Production ◽  
Protective Effects ◽  
Hypoxic Pulmonary Hypertension ◽  
Beneficial Effects ◽  
Anti Oxidant

Punicalagin (PG), a major bioactive ingredient in pomegranate juice, has been proven to have anti-oxidative stress properties and to exert protective effects on acute lung injuries induced by lipopolysaccharides. This study aimed to investigate the effects of PG treatment on hypoxic pulmonary hypertension (HPH) and the underlying mechanisms responsible for the effects. Rats were exposed to 10% oxygen for 2 wk (8 h/day) to induce the HPH model. PG (5, 15, 45[Formula: see text]mg/kg) was orally administered 10[Formula: see text]min before hypoxia each day. PG treatments at the doses of 15 and 45[Formula: see text]mg/kg/d decreased the mean pulmonary arterial pressure (mPAP) and alleviated right ventricular hypertrophy and vascular remodeling in HPH rats. Meanwhile, PG treatment attenuated the hypoxia-induced endothelial dysfunction of pulmonary artery rings. The beneficial effects of PG treatment were associated with improved nitric oxide (NO)-cGMP signaling and reduced oxidative stress, as evidenced by decreased superoxide generation, gp91[Formula: see text] expression and nitrotyrosine content in the pulmonary arteries. Furthermore, tempol’s scavenging of oxidative stress also increased NO production and attenuated endothelial dysfunction and pulmonary hypertension in HPH rats. Combining tempol and PG did not exert additional beneficial effects compared to tempol alone. Our study indicated for the first time that PG treatment can protect against hypoxia-induced endothelial dysfunction and pulmonary hypertension in rats, which may be induced via its anti-oxidant actions.

scholarly journals Shear stress induces Gαq/11 activation independently of G protein-coupled receptor activation in endothelial cells

2017 ◽  
Vol 312 (4) ◽  
pp. C428-C437 ◽  
Author(s):  
Nathaniel G. dela Paz ◽  
Benoît Melchior ◽  
John A. Frangos
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Fluid Shear Stress ◽  
Receptor Activation ◽  
Proximity Ligation Assay ◽  
Human Coronary Artery ◽  
Gpcr Activation ◽  
G Protein Coupled

Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay (PLA) to investigate the role of a specific GPCR/Gαq/11 pair in EC shear stress-induced mechanotransduction. We demonstrated that sphingosine 1-phosphate (S1P) stimulation causes a rapid dissociation at 0.5 min of Gαq/11 from its receptor S1P3, followed by an increased association within 2 min of GPCR kinase-2 (GRK2) and β-arrestin-1/2 with S1P3 in human coronary artery ECs, which are consistent with GPCR/Gαq/11 activation and receptor desensitization/internalization. The G protein activator AlF4 resulted in increased dissociation of Gαq/11 from S1P3, but no increase in association between S1P3 and either GRK2 or β-arrestin-1/2. The G protein inhibitor guanosine 5′-(β-thio) diphosphate (GDP-β-S) and the S1P3 antagonist VPC23019 both prevented S1P-induced activation. Shear stress also caused the rapid activation within 7 s of S1P3/Gαq/11. There were no increased associations between S1P3 and GRK2 or S1P3 and β-arrestin-1/2 until 5 min. GDP-β-S, but not VPC23019, prevented dissociation of Gαq/11 from S1P3 in response to shear stress. Shear stress did not induce rapid dephosphorylation of β-arrestin-1 or rapid internalization of S1P3, indicating no GPCR activation. These findings suggest that Gαq/11 participates in the sensing/transducing of shear stress independently of GPCR activation in ECs.

scholarly journals MIR503HG Loss Promotes Endothelial-to-Mesenchymal Transition in Vascular Disease

2021 ◽  
Author(s):  
João P. Monteiro ◽  
Julie Rodor ◽  
Axelle Caudrillier ◽  
Jessica P Scanlon ◽  
Ana-Mishel Spiroski ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Molecular Mechanisms ◽  
Clinical Samples ◽  
Vascular Remodelling ◽  
Mesenchymal Transition ◽  
Polypyrimidine Tract Binding Protein ◽  
Endothelial To Mesenchymal Transition

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodelling. However, the molecular mechanisms that govern this transition remain largely unknown, including the contribution of long non-coding RNAs (lncRNAs). Objective: To investigate the role of lncRNAs in EndMT and their relevance to vascular remodelling. Methods and Results: To study EndMT in vitro, primary endothelial cells (EC) were treated with transforming growth factor-β2 and interleukin-1β. Single-cell and bulk RNA-sequencing were performed to investigate the transcriptional architecture of EndMT and identify regulated lncRNAs. The functional contribution of seven lncRNAs during EndMT was investigated based on a DsiRNA screening assay. The loss of lncRNA MIR503HG was identified as a common signature across multiple human EC types undergoing EndMT in vitro. MIR503HG depletion induced a spontaneous EndMT phenotype, while its overexpression repressed hallmark EndMT changes, regulating 29% of its transcriptome signature. Importantly, the phenotypic changes induced by MIR503HG were independent of miR-424 and miR-503, which overlap the lncRNA locus. The pathological relevance of MIR503HG down-regulation was confirmed in vivo using Sugen/Hypoxia (SuHx)-induced pulmonary hypertension (PH) in mouse, as well as in human clinical samples, in lung sections and blood outgrowth endothelial cells (BOECs) from pulmonary arterial hypertension (PAH) patients. Overexpression of human MIR503HG in SuHx mice led to reduced mesenchymal marker expression, suggesting MIR503HG therapeutic potential. We also revealed that MIR503HG interacts with the Polypyrimidine Tract Binding Protein 1 (PTB1) and regulates its protein level. PTBP1 regulation of EndMT markers suggests that the role of MIR503HG in EndMT might be mediated in part by PTBP1. Conclusions: This study reports a novel lncRNA transcriptional profile associated with EndMT and reveals the crucial role of the loss of MIR503HG in EndMT and its relevance to pulmonary hypertension.

Vascular toxicity associated with anti-angiogenic drugs

2020 ◽  
Vol 134 (18) ◽  
pp. 2503-2520
Author(s):  
Karla B. Neves ◽  
Augusto C. Montezano ◽  
Ninian N. Lang ◽  
Rhian M. Touyz
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adenosine Diphosphate ◽  
No Production ◽  
Vascular Effects ◽  
Vegf Inhibitors ◽  
Vascular Toxicity ◽  
Endothelin System ◽  
Anti Cancer

Abstract Over the past two decades, the treatment of cancer has been revolutionised by the highly successful introduction of novel molecular targeted therapies and immunotherapies, including small-molecule kinase inhibitors and monoclonal antibodies that target angiogenesis by inhibiting vascular endothelial growth factor (VEGF) signaling pathways. Despite their anti-angiogenic and anti-cancer benefits, the use of VEGF inhibitors (VEGFi) and other tyrosine kinase inhibitors (TKIs) has been hampered by potent vascular toxicities especially hypertension and thromboembolism. Molecular processes underlying VEGFi-induced vascular toxicities still remain unclear but inhibition of endothelial NO synthase (eNOS), reduced nitric oxide (NO) production, oxidative stress, activation of the endothelin system, and rarefaction have been implicated. However, the pathophysiological mechanisms still remain elusive and there is an urgent need to better understand exactly how anti-angiogenic drugs cause hypertension and other cardiovascular diseases (CVDs). This is especially important because VEGFi are increasingly being used in combination with other anti-cancer dugs, such as immunotherapies (immune checkpoint inhibitors (ICIs)), other TKIs, drugs that inhibit epigenetic processes (histone deacetylase (HDAC) inhibitor) and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, which may themselves induce cardiovascular injury. Here, we discuss vascular toxicities associated with TKIs, especially VEGFi, and provide an up-to-date overview on molecular mechanisms underlying VEGFi-induced vascular toxicity and cardiovascular sequelae. We also review the vascular effects of VEGFi when used in combination with other modern anti-cancer drugs.

scholarly journals Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

2013 ◽  
Vol 50 (2) ◽  
pp. 229-241 ◽  
Author(s):  
Özlem Erdogdu ◽  
Linnéa Eriksson ◽  
Hua Xu ◽  
Åke Sjöholm ◽  
Qimin Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
P38 Mapk ◽  
Experimental Studies ◽  
Receptor Activation ◽  
No Production ◽  
Ros Production ◽  
Human Coronary Artery ◽  
Glucagon Like Peptide 1 ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7–36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7–36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

scholarly journals Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase

2011 ◽  
Vol 301 (3) ◽  
pp. L334-L345 ◽  
Author(s):  
Ru-Jeng Teng ◽  
Jianhai Du ◽  
Hao Xu ◽  
Ivane Bakhutashvili ◽  
Annie Eis ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Ex Vivo ◽  
No Production ◽  
Cellular Mechanisms ◽  
Dimer Formation ◽  
Enos Activity ◽  
Endothelial Nitric Oxide

Persistent pulmonary hypertension of the newborn (PPHN) is associated with decreased blood vessel density that contributes to increased pulmonary vascular resistance. Previous studies showed that uncoupled endothelial nitric oxide (NO) synthase (eNOS) activity and increased NADPH oxidase activity resulted in marked decreases in NO bioavailability and impaired angiogenesis in PPHN. In the present study, we hypothesize that loss of tetrahydrobiopterin (BH4), a critical cofactor for eNOS, induces uncoupled eNOS activity and impairs angiogenesis in PPHN. Pulmonary artery endothelial cells (PAEC) isolated from fetal lambs with PPHN (HTFL-PAEC) or control lambs (NFL-PAEC) were used to investigate the cellular mechanisms impairing angiogenesis in PPHN. Cellular mechanisms were examined with respect to BH4 levels, GTP-cyclohydrolase-1 (GCH-1) expression, eNOS dimer formation, and eNOS-heat shock protein 90 (hsp90) interactions under basal conditions and after sepiapterin (Sep) supplementation. Cellular levels of BH4, GCH-1 expression, and eNOS dimer formation were decreased in HTFL-PAEC compared with NFL-PAEC. Sep supplementation decreased apoptosis and increased in vitro angiogenesis in HTFL-PAEC and ex vivo pulmonary artery sprouting angiogenesis. Sep also increased cellular BH4 content, NO production, eNOS dimer formation, and eNOS-hsp90 association and decreased the superoxide formation in HTFL-PAEC. These data demonstrate that Sep improves NO production and angiogenic potential of HTFL-PAEC by recoupling eNOS activity. Increasing BH4 levels via Sep supplementation may be an important therapy for improving eNOS function and restoring angiogenesis in PPHN.

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

2013 ◽  
Vol 305 (12) ◽  
pp. L934-L942 ◽  
Author(s):  
Marijke Wynants ◽  
Leanda Vengethasamy ◽  
Alicja Ronisz ◽  
Bart Meyns ◽  
Marion Delcroix ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Inflammatory Marker ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-κB-mediated signal transduction. CRP-induced NF-κB activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-κB pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-κB kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-κBp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-κB pathway in mediating different effects of CRP on proximal CTEPH-PAEC.

scholarly journals The role of asymmetric dimethylarginine in the development of arterial hypertension.

2018 ◽  
Vol 95 (11) ◽  
pp. 965-970
Author(s):  
V. I. Podzolkov ◽  
T. A. Safronova ◽  
Dinara U. Natkina
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Asymmetric Dimethylarginine ◽  
Biological Marker ◽  
No Production ◽  
Nitric Oxide Synthase Inhibitor ◽  
Synthase Inhibitor

The results of numerous studies of recent decades confirm the crucial role of vascular endothelium in regulating vascular homeostasis. A plethora of recent studies have shed light on the clinical significance of endothelial dysfunction in essential hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. At present, it is considered as a generally recognized marker of endothelial dysfunction by most researchers. In vitro experiments showed that ADMA inhibits endothelium-dependent arterial relaxation, increases the level of indicators characterizing the degree of oxidative stress in endothelial cells, enhances the synthesis of the superoxide anion radical by endothelial cells. The molecular mechanisms described above, activated with an increase in the concentration of ADMA, cause various disturbances in the function of the cardiovascular system, which gave grounds to consider the level of ADMA as a criterion and risk factor for the development of cardiovascular diseases. Thus, ADMA plays a key role in the development and progression of CVD associated with a spectrum of diseases and pathological conditions characterized by a disturbance in NO production. Despite clinical and experimental confirmation of the relationship between the increase in ADMA in plasma and the development of cardiovascular events, the unambiguous etiopathogenetic role of ADMA in CVD requires further research. In order to accurately answer the question of whether ADMA is an etiological factor or a biological marker of CVD, additional analysis is needed to study the biochemical, genetic and pharmacological aspects of ADMA metabolism, the results of which are presented in this article.

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