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Article: Role of Erythrocytes in Nitric Oxide Metabolism and Paracrine Regulation of Endothelial Function.

Gajecki, Damian / Gawryś, Jakub / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

2022 Volume 11, Issue 5

Abstract: Emerging studies provide new data shedding some light on the complex and pivotal role of red blood cells (RBCs) in nitric oxide (NO) metabolism and paracrine regulation of endothelial function. NO is involved in the regulation of vasodilatation, platelet ...

Abstract	Emerging studies provide new data shedding some light on the complex and pivotal role of red blood cells (RBCs) in nitric oxide (NO) metabolism and paracrine regulation of endothelial function. NO is involved in the regulation of vasodilatation, platelet aggregation, inflammation, hypoxic adaptation, and oxidative stress. Even though tremendous knowledge about NO metabolism has been collected, the exact RBCs' status still requires evaluation. This paper summarizes the actual knowledge regarding the role of erythrocytes as a mobile depot of amino acids necessary for NO biotransformation. Moreover, the complex regulation of RBCs' translocases is presented with a particular focus on cationic amino acid transporters (CATs) responsible for the NO substrates and derivatives transport. The main part demonstrates the intraerythrocytic metabolism of L-arginine with its regulation by reactive oxygen species and arginase activity. Additionally, the process of nitrite and nitrate turnover was demonstrated to be another stable source of NO, with its reduction by xanthine oxidoreductase or hemoglobin. Additional function of hemoglobin in NO synthesis and its subsequent stabilization in steady intermediates is also discussed. Furthermore, RBCs regulate the vascular tone by releasing ATP, inducing smooth muscle cell relaxation, and decreasing platelet aggregation. Erythrocytes and intraerythrocytic NO metabolism are also responsible for the maintenance of normotension. Hence, RBCs became a promising new therapeutic target in restoring NO homeostasis in cardiovascular disorders.
Language	English
Publishing date	2022-05-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11050943
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Cardiovascular Risk and Endothelial Dysfunction in Primary Sjogren Syndrome Is Related to the Disease Activity

Łuczak, Anna / Małecki, Rafał / Kulus, Michał / Madej, Marta / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Nutrients. 2021 June 17, v. 13, no. 6

2021

Abstract: The aim of our study was to evaluate if endothelial-dysfunction (ED) occurs in patients with primary Sjogren syndrome (pSS) and whether it is associated with the disease characteristics and activity. A total of 46 patients with pSS and 30 controls, ... ...

Abstract	The aim of our study was to evaluate if endothelial-dysfunction (ED) occurs in patients with primary Sjogren syndrome (pSS) and whether it is associated with the disease characteristics and activity. A total of 46 patients with pSS and 30 controls, without known cardiovascular disease, were enrolled in this study. A flow-mediated-dilation (FMD) of the brachial artery, plasma concentrations of the nitric oxide (NO) metabolic pathway (ADMA, L-arginine, SDMA, cGMP), and markers of endothelial inflammatory function (PAI-1, sE-selectin) and angiogenesis (angiostatin, VEGF) were analyzed. The FMD was significantly lower in pSS patients (7.56 ± 3.08 vs. 10.91 ± 1.02%, p = 0.043) and positively correlated with the Ro/SS-A-antibodies (r = 0.34, p = 0.03), pulmonary involvement (r = 0.52, p = 0.001) and inversely with ADMA (r = −0.35, p = 0.04). Plasma ADMA, L-arginine and angiostatin levels were significantly higher in pSS patients (0.39 ± 0.08 vs. 0.36 ± 0.06 µmol/L, p = 0.05; 29.07 ± 6.7 vs. 25.4 ± 5.23 µmol/L, p = 0.01; 152.25 ± 60.99 vs. 120.07 ± 38.7 pg/mL, p = 0.0, respectively). ADMA was associated with ESSDAI (r = 0.33, p = 0.02), SCORE (r = 0.57, p = 0.00003) and focus score (r = 0.38, p = 0.04). In the multiple regression analysis, the ESSDAI was significantly and independently associated with plasma ADMA levels (β = 0.24, p = 0.04). Moreover, plasma cGMP concentrations were negatively correlated with the disease duration (r = −0.31, p = 0.03). Endothelial function is impaired in patients with pSS and associated with the measures of disease activity, which supports the key-role of inflammation in developing and maintaining accelerated atherosclerosis.
Keywords	angiogenesis ; arginine ; atherosclerosis ; biochemical pathways ; inflammation ; nitric oxide ; regression analysis ; risk
Language	English
Dates of publication	2021-0617
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13062072
Database	NAL-Catalogue (AGRICOLA)

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Article: A Cross-Talk between the Erythrocyte L-Arginine/ADMA/Nitric Oxide Metabolic Pathway and the Endothelial Function in Subjects with Type 2 Diabetes Mellitus

Gajecki, Damian / Gawryś, Jakub / Wiśniewski, Jerzy / Fortuna, Paulina / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Nutrients. 2021 July 04, v. 13, no. 7

2021

Abstract: 1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are ... ...

Abstract	(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.
Keywords	arginine ; biochemical pathways ; citrulline ; cross-sectional studies ; erythrocytes ; nitric oxide ; noninsulin-dependent diabetes mellitus
Language	English
Dates of publication	2021-0704
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13072306
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Article ; Online: Novel Molecular Mechanisms of Pulmonary Hypertension: A Search for Biomarkers and Novel Drug Targets-From Bench to Bed Site.

Gajecki, Damian / Gawrys, Jakub / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Oxidative medicine and cellular longevity

2020 Volume 2020, Page(s) 7265487

Abstract: Pulmonary hypertension (PH) is defined as increased mean pulmonary artery pressure (mPAP) above 25 mmHg, measured at rest by right heart catheterization. The exact global prevalence of PH is difficult to estimate, mainly due to the complex aetiology, and ...

Abstract	Pulmonary hypertension (PH) is defined as increased mean pulmonary artery pressure (mPAP) above 25 mmHg, measured at rest by right heart catheterization. The exact global prevalence of PH is difficult to estimate, mainly due to the complex aetiology, and its spread may be underestimated. To date, numerous studies on the aetiology and pathophysiology of PH at molecular level were conducted. Simultaneously, some clinical studies have shown potential usefulness of well-known and widely recognized cardiovascular biomarkers, but their potential clinical usefulness in diagnosis and management of PH is poor due to their low specificity accompanied with numerous other cardiovascular comorbidities of PH subjects. On the other hand, a large body of basic research-based studies provides us with novel molecular pathomechanisms, biomarkers, and drug targets, according to the evidence-based medicine principles. Unfortunately, the simple implementation of these results to clinical practice is impossible due to a large heterogeneity of the PH pathophysiology, where the clinical symptoms constitute only a common denominator and a final result of numerous crosstalking metabolic pathways. Therefore, future studies, based mostly on translational medicine, are needed in order to both organize better the pathophysiological classification of various forms of PH and define precisely the optimal diagnostic markers and therapeutic targets in particular forms of PH. This review paper summarizes the current state of the art regarding the molecular background of PH with respect to its current classification. Novel therapeutic strategies and potential biomarkers are discussed with respect to their limitations in use in common clinical practice.
MeSH term(s)	Biomarkers/metabolism ; Epigenesis, Genetic ; Humans ; Hypertension, Pulmonary/genetics ; Molecular Targeted Therapy ; Mutation/genetics ; Translational Medical Research
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-05-22
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1942-0994
ISSN (online)	1942-0994
DOI	10.1155/2020/7265487
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Article ; Online: Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders.

Gawrys, Jakub / Gajecki, Damian / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Oxidative medicine and cellular longevity

2020 Volume 2020, Page(s) 1015908

Abstract: Despite the development of new drugs and other therapeutic strategies, cardiovascular disease (CVD) remains still the major cause of morbidity and mortality in the world population. A lot of research, performed mostly in the last three decades, revealed ... ...

Abstract	Despite the development of new drugs and other therapeutic strategies, cardiovascular disease (CVD) remains still the major cause of morbidity and mortality in the world population. A lot of research, performed mostly in the last three decades, revealed an important correlation between "classical" demographic and biochemical risk factors for CVD, (i.e., hypercholesterolemia, hyperhomocysteinemia, smoking, renal failure, aging, diabetes, and hypertension) with endothelial dysfunction associated directly with the nitric oxide deficiency. The discovery of nitric oxide and its recognition as an endothelial-derived relaxing factor was a breakthrough in understanding the pathophysiology and development of cardiovascular system disorders. The nitric oxide synthesis pathway and its regulation and association with cardiovascular risk factors were a common subject for research during the last decades. As nitric oxide synthase, especially its endothelial isoform, which plays a crucial role in the regulation of NO bioavailability, inhibiting its function results in the increase in the cardiovascular risk pattern. Among agents altering the production of nitric oxide, asymmetric dimethylarginine-the competitive inhibitor of NOS-appears to be the most important. In this review paper, we summarize the role of L-arginine-nitric oxide pathway in cardiovascular disorders with the focus on intraplatelet metabolism.
MeSH term(s)	Amidohydrolases/metabolism ; Arginine/analogs & derivatives ; Arginine/blood ; Arginine/metabolism ; Blood Platelets/metabolism ; Cardiovascular Diseases/blood ; Cardiovascular Diseases/metabolism ; Endothelium, Vascular/metabolism ; Humans ; Metabolic Networks and Pathways ; Nitric Oxide/blood ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitric Oxide Synthase/metabolism ; Risk Factors
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; N,N-dimethylarginine (63CV1GEK3Y) ; Arginine (94ZLA3W45F) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Amidohydrolases (EC 3.5.-) ; dimethylargininase (EC 3.5.3.18)
Language	English
Publishing date	2020-03-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2455981-7
ISSN	1942-0994 ; 1942-0994
ISSN (online)	1942-0994
ISSN	1942-0994
DOI	10.1155/2020/1015908
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cardiovascular Disorders Triggered by Obstructive Sleep Apnea-A Focus on Endothelium and Blood Components.

Mochol, Jakub / Gawrys, Jakub / Gajecki, Damian / Szahidewicz-Krupska, Ewa / Martynowicz, Helena / Doroszko, Adrian

International journal of molecular sciences

2021 Volume 22, Issue 10

Abstract: Obstructive sleep apnea (OSA) is known to be an independent cardiovascular risk factor. Among arousal from sleep, increased thoracic pressure and enhanced sympathetic activation, intermittent hypoxia is now considered as one of the most important ... ...

Abstract	Obstructive sleep apnea (OSA) is known to be an independent cardiovascular risk factor. Among arousal from sleep, increased thoracic pressure and enhanced sympathetic activation, intermittent hypoxia is now considered as one of the most important pathophysiological mechanisms contributing to the development of endothelial dysfunction. Nevertheless, not much is known about blood components, which justifies the current review. This review focuses on molecular mechanisms triggered by sleep apnea. The recurrent periods of hypoxemia followed by reoxygenation promote reactive oxygen species (ROS) overproduction and increase inflammatory response. In this review paper we also intend to summarize the effect of treatment with continuous positive airway pressure (CPAP) on changes in the profile of the endothelial function and its subsequent potential clinical advantage in lowering cardiovascular risk in other comorbidities such as diabetes, atherosclerosis, hypertension, atrial fibrillation. Moreover, this paper is aimed at explaining how the presence of OSA may affect platelet function and exert effects on rheological activity of erythrocytes, which could also be the key to explaining an increased risk of stroke.
MeSH term(s)	Animals ; Cardiovascular Diseases/etiology ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/pathology ; Continuous Positive Airway Pressure ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Erythrocytes/metabolism ; Erythrocytes/pathology ; Humans ; Hypoxia/physiopathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Sleep Apnea, Obstructive/complications ; Sleep Apnea, Obstructive/metabolism ; Sleep Apnea, Obstructive/pathology
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2021-05-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22105139
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Article ; Online: Cardiovascular Risk and Endothelial Dysfunction in Primary Sjogren Syndrome Is Related to the Disease Activity.

Łuczak, Anna / Małecki, Rafał / Kulus, Michał / Madej, Marta / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Nutrients

2021 Volume 13, Issue 6

Abstract	The aim of our study was to evaluate if endothelial-dysfunction (ED) occurs in patients with primary Sjogren syndrome (pSS) and whether it is associated with the disease characteristics and activity. A total of 46 patients with pSS and 30 controls, without known cardiovascular disease, were enrolled in this study. A flow-mediated-dilation (FMD) of the brachial artery, plasma concentrations of the nitric oxide (NO) metabolic pathway (ADMA, L-arginine, SDMA, cGMP), and markers of endothelial inflammatory function (PAI-1, sE-selectin) and angiogenesis (angiostatin, VEGF) were analyzed. The FMD was significantly lower in pSS patients (7.56 ± 3.08 vs. 10.91 ± 1.02%,
MeSH term(s)	Adult ; Arginine/metabolism ; Biomarkers/blood ; Brachial Artery ; Cardiovascular Diseases/complications ; Endothelium, Vascular ; Female ; Heart Disease Risk Factors ; Humans ; Inflammation/metabolism ; Male ; Middle Aged ; Regression Analysis ; Sjogren's Syndrome/complications ; Vascular Diseases/complications
Chemical Substances	Biomarkers ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2021-06-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13062072
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Article: Effect of the Renin-Angiotensin-Aldosterone System Reactivity on Endothelial Function and Modulative Role of Valsartan in Male Subjects with Essential Hypertension.

Jasiczek, Jakub / Trocha, Małgorzata / Derkacz, Arkadiusz / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Journal of clinical medicine

2021 Volume 10, Issue 24

Abstract: Background: The aim of the study was to evaluate the relationship between renin-angiotensin-aldosterone (RAA) system activity and reactivity, and the endothelial function profile in normotensive subjects (N), and in essential hypertensives (H), followed ...

Abstract	Background: The aim of the study was to evaluate the relationship between renin-angiotensin-aldosterone (RAA) system activity and reactivity, and the endothelial function profile in normotensive subjects (N), and in essential hypertensives (H), followed by analysis of the modulatory role of an angiotensin receptor blocker (ARB): valsartan, administered in the management of hypertension. Methods: A total of 101 male subjects were enrolled to the study: 31H and 70N. The nitric-oxide (NO) bioavailability (l-Arginine, asymmetric dimethylarginine (ADMA)), symmetric dimethylarginine (SDMA), endothelial vasodilative function (flow mediated dilation (FMD)), oxidative-stress markers (malonyldialdehyde (MDA), thiol index (GSH/GSSG), nitrotyrozine ( Results: No effect of valsartan and ASA on the flow-mediated vasodilation (FMD) and the NO bioavailability in hypertensives was observed. Administration of valsartan increased plasma renin activity (PRA), but without a decrease in the aldosterone levels. ASA treatment minimized the pre-existing differences between the groups, and increased the PRA in the N-subgroup with the highest ARR values. The blood concentrations of proinflammatory sICAM-1, sE-selectin, sVCAM-1, and PAI-1 were higher, whereas the anti-inflammatory 6-keto-PGF1 alpha level was lower in hypertensive subjects. The levels of angiogenic VEGF did not differ between groups. Conclusions: Our study does not confirm the modulative effect of valsartan on endothelial function. Normotensive men showed an increase in FMD after l-arginine administration, possibly indicating baseline impairment of the NO synthesis.
Language	English
Publishing date	2021-12-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10245816
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Article ; Online: A Cross-Talk between the Erythrocyte L-Arginine/ADMA/Nitric Oxide Metabolic Pathway and the Endothelial Function in Subjects with Type 2 Diabetes Mellitus.

Gajecki, Damian / Gawryś, Jakub / Wiśniewski, Jerzy / Fortuna, Paulina / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

Nutrients

2021 Volume 13, Issue 7

Abstract	(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Arginine/analogs & derivatives ; Arginine/blood ; Citrulline/blood ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/blood ; Endothelium, Vascular/metabolism ; Erythrocytes/metabolism ; Female ; Humans ; Male ; Metabolic Networks and Pathways ; Middle Aged ; Nitric Oxide/blood
Chemical Substances	Citrulline (29VT07BGDA) ; Nitric Oxide (31C4KY9ESH) ; N,N-dimethylarginine (63CV1GEK3Y) ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2021-07-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13072306
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Article ; Online: The Human Carbonic Anhydrase II in Platelets: An Underestimated Field of Its Activity.

Jakubowski, Maciej / Szahidewicz-Krupska, Ewa / Doroszko, Adrian

BioMed research international

2018 Volume 2018, Page(s) 4548353

Abstract: Carbonic anhydrases constitute a group of enzymes that catalyse reversible hydration of carbon dioxide leading to the formation of bicarbonate and proton. The platelet carbonic anhydrase II (CAII) was described for the first time in the '80s of the last ... ...

Abstract	Carbonic anhydrases constitute a group of enzymes that catalyse reversible hydration of carbon dioxide leading to the formation of bicarbonate and proton. The platelet carbonic anhydrase II (CAII) was described for the first time in the '80s of the last century. Nevertheless, its direct role in platelet physiology and pathology still remains poorly understood. The modulation of platelet CAII action as a therapeutic approach holds promise as a novel strategy to reduce the impact of cardiovascular diseases. This short review paper summarises the current knowledge regarding the role of human CAII in regulating platelet function. The potential future directions considering this enzyme as a potential drug target and important pathophysiological chain in platelet-related disorders are described.
MeSH term(s)	Bicarbonates ; Blood Platelets/physiology ; Carbonic Anhydrase II/physiology ; Carbonic Anhydrases ; Humans ; Protons
Chemical Substances	Bicarbonates ; Protons ; Carbonic Anhydrase II (EC 4.2.1.-) ; Carbonic Anhydrases (EC 4.2.1.1)
Language	English
Publishing date	2018-06-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2018/4548353
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