Activity modulation of various nitric oxide syntases as an approach to endothelial dysfunction therapy

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Abstract

Nitric oxide as a therapeutic approach to the treatment of cardiovascular diseases attracted the attention of researchers at the end of the 19th century. As a vasodilator, nitric oxide may be a unique therapeutic agent for the treatment of hypertension and, as a result, renal failure and left ventricular hypertrophy.

The aim of the article is to analyze the literature data on possible ways of modulating the activity of various nitric oxide synthases as an approach to the treatment of endothelial dysfunction.

Materials and methods. When searching for materials for writing a review article, such abstract databases as PubMed, Google Scholar, e-Library, etc., were used. The search was carried out on the publications for the period from 1990 to 2021. The following words and phrases were chosen as parameters for the literature selection: nitric oxide; NO synthase; endothelial dysfunction; NO synthase activator; NO synthase inhibitor.

The following words and phrases were chosen as parameters for the literature selection:

Results. The article presents the history of the nitric oxide discovery and its biological role, the process of its biosynthesis, as well as the isoforms of its synthesizing enzymes (NOS): neuronal – nNOS, endothelial – eNOS and inducible iNOS, and their role in normal and pathological physiology. The process of NOS uncoupling (its molecular mechanisms) has been considered as the basis of endothelial dysfunction.

The examples of the pharmacological correction (BH4, arginase inhibitors, statins, resveratrol) are presented. In addition, NO synthase activators (calcium dobesilate, cavNOxin, and some NOS transcription activators), as well as non-selective (L-NMMA, 1-NNA, L-NAME, ADMA, 546C88, VAS203) and selective (L-NIO, 7-nitroindazole, aminoguanidine, L-NIL, GW273629, GW274150, cavtratin) inhibitors of nitric oxide synthasehave been described.

Conclusion. Nitric oxide synthases continue to be promising targets for the development of agents that modulate their activity to correct various pathologies. As a therapeutic approach, modulation of the nitric oxide synthase activity can be implemented to treat endothelial dysfunction, which is the cause for complications of many diseases.

About the authors

Denis V. Kurkin

Volgograd State Medical University

Author for correspondence.
Email: strannik986@mail.ru
ORCID iD: 0000-0002-1116-3425

Doctor of Sciences (Pharmacy), Associate Professor, Professor of the Department of Clinical Pharmacology and Intensive Care, First Deputy Director of the Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Elizaveta E. Abrosimova

Volgograd State Medical University

Email: abrosimova.volgmed@gmail.com
ORCID iD: 0000-0002-6472-6906

post-graduate student of the Department of Pharmacology and Pharmacy, Institute of Continuing Medical and Pharmaceutical Education

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Dmitry A. Bakulin

Volgograd State Medical University

Email: mbfdoc@gmail.com
ORCID iD: 0000-0003-4694-3066

Candidate of Sciences (Medicine), Senior Researcher, Laboratory of Pharmacology of Cardiovascular Drugs, Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Nikolai S. Kovalev

Volgograd State Medical University

Email: kovalev.volgmed@gmail.com

post-graduate student of the Department of Pharmacology and Pharmacy, Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Marina A. Dubrovina

Volgograd State Medical University

Email: dubrovina.volgmed@gmail.com
ORCID iD: 0000-0003-1903-8589

post-graduate student of the Department of Pharmacology and Pharmacy, Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Aleksandr V. Borisov

Volgograd State Medical University

Email: borissow1978@rambler.ru
ORCID iD: 0000-0003-0202-0008

Researcher, Laboratory of Pharmacology of Cardiovascular Drugs, Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Andrey V. Strygin

Volgograd State Medical University

Email: drumsav@mail.ru
ORCID iD: 0000-0002-6997-1601

Candidate of Sciences (Medicine), Associate Professor, Deputy Director of the Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Evgeniy I. Morkovin

Volgograd State Medical University

Email: e.i.morkovin@gmail.com
ORCID iD: 0000-0002-7119-3546

Candidate of Sciences (Medicine), Associate Professor, Head of the Laboratory of Neuropsychopharmacology, Research Center of Innovative Pharma Products

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Ivan N. Tyurenkov

Volgograd State Medical University

Email: fibfuv@mail.ru
ORCID iD: 0000-0001-7574-3923

Doctor of Sciences (Medicine), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Pharmacology of Cardiovascular Drugs, Research Center of Innovative Pharma Products, Head of the Department of Pharmacology and Pharmacy, Institute of Continuing Medical and Pharmaceutical Education

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

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2. Figure 1 – Schematic pathway for NO synthesis, including enzymatic (via NOS; main pathway) and non-enzymatic pathways (A), structure and mechanism of NOS (B, C) action. Note. A) The important sources of NO include a NOS activity and a nitrite reduction (NO2-) under hypoxic and acidic conditions. NO reacts with superoxide (O2-) to form peroxynitrite (ONOO-). Superoxide can be obtained from several sources, including a mitochondrial activity and a NADPH oxidase (NOX) activity. When protonated or combined with carbon dioxide (CO2), peroxynitrite produces a range of free radicals, including nitrogen dioxide (NO2) as well as hydroxyl (OH) and carbonate (CO3-) radicals. NO reacts with metals such as iron (FeII) to form metal nitrosyls (FeIINO) such as the one found in soluble guanylate cyclase. NO also reacts with molecular oxygen to form nitrogen dioxide and nitrogen trioxide. Together, these particles can participate in oxidative (such as thiol oxidation) reactions, nitrosation (thiol nitrosation, RSNO) and nitration (tyrosine nitration, NO2 Tyr) of biological targets; B) NOS monomers are able to transfer electrons from reduced NADPH to FAD and FMN and have a limited ability to reduce molecular oxygen to superoxide (O2-). Monomers and isolated reductase domains can bind calmodulin (CaM), which enhances the electron transfer within the reductase domain. NOS monomers are unable to bind the BH4 cofactor or the substrate L-arginine and cannot catalyze the NO production; B) In the presence of heme, NOS can form a functional dimer. Heme is required for а cross-domain electron transfer from flavins to heme of the opposite monomer. Adapted from [17(а) и 21(b и c)].

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3. Figure 2 – Synthesis, recycling and oxidation of BH4 as the determinant of NOS uncoupling. Note. On the left: Under normal conditions, BH4 bioavailability is maintained by de novo synthesis from guanosine triphosphate (GTP) in which the rate limiting step is catalyzed by GTP cyclohydrolase (GTPCH) by dihydrofolate reductase (DHFR) mediated recycling of 7,8-dihydrobiopterin (BH2), the primary product of a non-enzymatic oxidation of BH4. On the right: “Unbound” NOS are characterized by the formation of superoxide (O2-). NOS сleavage is facilitated by a decrease in the bioavailability of BH4 relative to the BH2 or NOS protein. In turn, O2- formed by unbound NOS, reacts with NO to form peroxynitrite (ONOO-), a highly reactive anion that rapidly oxidizes BH4. Hence, the NOS uncoupling state is stabilized by the self-propagating oxidative stress. In addition to this primary BH4-mediated cycle, additional mechanisms have been shown to promote uncoupling, including a reduced arginine bioavailability, high levels of oxidized glutathione (GSSG) compared to reduced glutathione (GSH), or elevated concentrations of endogenous NOS inhibitors LN-monomethylarginine (L-NMMA, monomethyl-L-arginine) and asymmetric dimethylarginine (ADMA). Adapted from [60].

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4. Figure 3 – Pathological conditions and mechanisms of NOS uncoupling. Note. Hypercholesterolemia, hypertension, smoking, and diabetes mellitus lead to the activation of NADPH (a reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, partially by a protein kinase C (PKC)-dependent mechanism. Diabetes mellitus also stimulates the production of mitochondrial ROS, that then triggers the activation of NADPH oxidase, which can increase a mitochondrial production of superoxide (O2-) and xanthine oxidase. The endothelial NO synthase (eNOS) enzyme can be uncoupled through two main mechanisms: deficiency of the BH4 cofactor or the L-arginine substrate. O2·- reacts with NO to form peroxynitrite (ONOO-). ONOO- oxidizes BH4 resulting in BH4 deficiency. L-arginine deficiency is caused by an increase in the arginase expression and activity, partially through RhoA/ROCK-dependent mechanisms. Unbound eNOS produces superoxide, thereby increasing the oxidative stress. The eNOS uncoupling reduces the endothelial NO production, which is further exacerbated by a decrease in the eNOS expression and activity. In addition to the population-level risk factors, the impaired blood flow makes arterial bifurcations and lateral branches prone to atherosclerosis. The increased oxidative stress and reduced endothelial NO production contribute significantly to the increased atherosclerosis in these areas. Adapted from [58].

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5. Figure 4 – Schematic representation of known causes and methods for correcting NOS uncoupling in the cardiovascular system. Note. Causes for NOS uncoupling are shown in red and treatments are shown in blue. Superoxide (O2-) or peroxynitrite (ONOO-) can oxidize BH4 to BH2, which can be prevented by antioxidants or NADPH oxidase inhibitors, and interfere with s-glutathionylation (s-Glu). Folic acid can stimulate dihydrofolate reductase (DHFR) to reduce BH2 to BH4. Arginase inhibition can preserve L-arginine levels to make it available to the NOS enzime. Adapted from [59].

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6. Figure 5 – Effect of statins on eNOS in endothelial cells. Note. By inhibiting mevalonate synthesis, statins reduce GGPP levels, prevent the Rho/ROCK activation and stabilize eNOS mRNA, thereby increasing the eNOS expression. By reducing caveolin-1 and circulating ADMA, as well as increasing eNOS phosphorylation at the Ser-633 and Ser-1177 activation sites via AMPK, Akt, and PKA, statins also increase the eNOS activity. Finally, by upregulating GTPCH, statins increase endothelial BH4, the presence and restoration of eNOS binding. GGPP is geranylgeranyl pyrophosphate; ROCK – Rho-associated protein kinase; GTPCH – guanosine triphosphate cyclohydrolase; AMPK 2 adenosine monophosphate activated protein kinase; PKA, protein kinase A; PI3K – phosphatidylinositide-3-kinase; ADMA - asymmetric dimethylarginine. Adapted from [77].

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7. Figure 6 – List of the most important inhibitors based on arginine. Note. Adapted from [92].

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8. Figure 7 – Resveratrol targets to prevent NOS uncoupling (80 adapted). Note. Resveratrol increases the NO production and prevents its breakdown. Resveratrol can activate sirtuin 1 (SIRT1) either directly (in a substrate-dependent manner) or indirectly (by inhibiting phosphodiesterases). SIRT1 stimulates endothelial NOS via deacetylation, enhances the eNOS expression via deacetylation of the forkhead box protein O1 (FOXO) transcription factor, and prevents the eNOS uncoupling by increasing the activity of GTP-cyclohydrolase I (GTPCH-I), a limiting factor in BH4 biosynthesis. AMPK and nuclear factor 2 associated with Nrf2 are indirect targets of resveratrol. AMPK phosphorylates eNOS by serine 1177. eNOS can also be phosphorylated by Erk1/2, which is stimulated by a pathway involving the estrogen receptor (ER) and the Src family tyrosine kinase. Caveolin-1 (Cav-1) is a protein that negatively regulates the eNOS activity. ADMA is an endogenous eNOS inhibitor that is cleaved by DDAH. The targets for the activation of dimethylarginine dimethylaminohydrolase (DDAH) or inhibition of NADPH oxidase have not been identified yet. Adapted from [80].

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Copyright (c) 2022 Kurkin D.V., Abrosimova E.E., Bakulin D.A., Kovalev N.S., Dubrovina M.A., Borisov A.V., Strygin A.V., Morkovin E.I., Tyurenkov I.N.

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