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15# Research Results in Pharmacology
Research Results in Pharmacology 5(3): 67-77 UDC: 615.065+616.053.2 DOI 10.3897/rrpharmacology. 5.39521
3 Research Article
Search for new pharmacological targets for increasing the efficiency of correction of cardiovascular diseases
Liliya V. Korokina1, Ivan V. Golubev2, Olga N. Pokopejko3, Anastasia V. Zagrebelnaya1, Sergey A. Demchenko1
1 Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia
2 Kursk City Clinical Maternity Hospital, 10 Pirogova St., Kursk, 305016, Russia
3 I.M. Sechenov First Moscow State Medical University, 2 B. Pirogovskaya St., Moscow, 19435, Russia
Corresponding author: Liliya V. Korokina ([email protected])
Academic editor: TatyanaPokrovskaya ♦ Received 1August2019 ♦ Accepted 2 September 2019 ♦ Published 30 September2019
Citation: Korokina LV, Golubev IV, Pokopejko ON, Zagrebelnaya AV, Demchenko SA (2019) Search for new pharmacological targets for increasing the efficiency of correction of cardiovascular diseases. Research Results in Pharmacology 5(3): 67-77. https:// doi.org/10.3897/rrpharmacology. 5.39521
Abstract
Introduction: Cardiovascular disease (CVD) is the leading cause of death worldwide: no other reason causes as many deaths a year as CVD. An estimated 17.9 million people died of CVD in 2016, accounting for 31% of all deaths in the world. People with CVD or at high risk for these diseases (due to one or more risk factors, such as high blood pressure, diabetes, hyperlipidemia, or an already developed disease) need early detection and assistance through counseling and, if necessary, taking medication.
Ways to find new targets for the correction of endothelium-associated pathology: The basis of the modern therapy for arterial hypertension and other cardiovascular diseases is the postulate of the need to correct endothelial dysfunction as an indication of the adequacy of antihypertensive and other types of treatment. Lowering blood pressure (BP) without normalizing endothelial function cannot be considered a successfully resolved clinical task. Currently, there are no drugs for specific pharmacological correction of endothelial dysfunction in cardiovascular diseases, and the search for new targets for pharmacological correction of endothelial dysfunction is one of the main tasks of pharmacology.
Keywords
endothelial dysfunction, pharmacological correction, target, nitric oxide.
Introduction
Cardiovascular diseases continue to be the leading cause of death and disability, which necessitates the need for an in-depth study of the pathogenesis and the development of treatment and prevention measures.
In the modern world, especially in developed countries, arterial hypertension (AH) is one of the main fac-
tors that increase disability and mortality due to such severe complications as myocardial infarction, heart failure and stroke. In Russia, the prevalence of hypertension among the adult population exceeds 30%, which makes the country a leader in Europe in mortality from strokes and coronary artery disease. One of the main causes of
Copyright Korokina LVetal. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
hypertension is endothelial dysfunction (ED), in the first place - impaired relaxation properties of the endothelium.
The basis of modern therapy of arterial hypertension and other cardiovascular diseases is the postulate of the need to correct endothelial dysfunction as an indicator of the adequacy of antihypertensive and other types of treatment. In fact, this means that a decrease in BP without normalizing endothelial function cannot be considered a successfully solved clinical task (Kyoung and Woo 2012).
"ADMA-eNOS" as a pharmacological target is of undoubted interest and has been the object of pharmacological studies (Gumanova et al. 2007, Jiang et al. 2016, Korokina et al. 2009, Korokin et al. 2011, Kostina et al. 2016, Pokrovskii et al. 2006, Pokrovskii et al. 2008, Pokrovskii et al. 2011, Pokrovskii et al. 2012, Pokrovskaya et al. 2007, Voronkov et al. 2008, Tsepeleva et al. 2011, Tyu-renkov and Voronkov 2008, Tyurenkov et al 2009, Sha-belnikova et al. 2015, Shakhno et al. 2017, Yakushev and Pokrovskii 2016). The studies have revealed the role of methylated derivatives of L-arginine - monomethy-larginine (L-NMMA) and asymmetric dimethylarginine (ADMA) as endogenous inhibitors of endothelial NO synthase (eNOS).
Earlier studies showed that preventing the accumulation and overcoming of inhibition of eNOS by an already established ADMA can be one of the ways to pharmacologically correct endothelial dysfunction. Endothelium protective properties realized by reducing the inhibitory effect of ADMA on eNOS agents, such as L-arginine (Pokrovskii et al. 2008), tetrahydrobiopterin, non-selective arginase inhibitor L-norvaline, and selective arginase II inhibitors (Yakushev and Pokrovskii 2016), etc., were experimentally confirmed.
It has also been established that systemic inflammatory diseases, by increasing the level of oxidative stress, lead to the formation of oxidized forms of high-density circulating lipoprotein. The accumulation of lipid peroxidation products may adversely affect the function of endothelial cells, but the basic mechanisms of this state, as well as the possibilities for its correction, remain unclear (Pérez et al. 2019).
Along with the accumulation of knowledge about the pathways of metabolic disorders of nitric oxide, the methods for assessing endothelial dysfunction also change. Numerous in vivo or in vitro, as well as invasive or non-invasive methods are used to study endothelial function. A number of methods widely used in clinical studies cannot be used for diagnostic purposes because of their invasiveness, high cost, and complex standardization. A number of authors propose further research and investment in this area to make these methods applicable in clinical practice and, therefore, to minimize the public health problems associated with cardiovascular diseases by early diagnosis of endothelial dysfunction and early correction of nitric oxide metabolism (Steppan et al. 2013).
However, currently there are no drugs for specific pharmacological correction of the metabolic pathway L-arginine-eNOS-nitric oxide, whose disorders are a uni-
versal and fundamental trigger mechanism for initiating a cascade of metabolic disorders leading to arterial hypertension and other diseases of the cardiovascular system.
Methods to improve and restore endothelial dysfunction in various pathological conditions are being intensively studied. The data from clinical studies of drugs that improve endothelial dysfunction are shown in Table 1.
This article is aimed at making the case for possible ways to search for new targets for the pharmacological correction of endothelial dysfunction.
The role of NOX1 and NOX2 oxidases in the pharmacological correction of endothelial dysfunction
The study of endothelium-dependent vasodilation began with the observation that the removal of endothelial cells from isolated arteries prevented the vasodilatory response to the introduction of acetylcholine. Various vasoactive substances, such as ligands of the G-protein-conjugated receptors, exhibit a similar inducing effect on vasodilation. Endothelium-dependent vasodilation is caused by the release of prostacyclin PGI2 and nitrogen monoxide (NO) or endothelial hyperpolarization factors (for example, H2O2) (Kvietys and Granger 2012). Dilation of isolated arteries caused by agonists or the bloodstream is blocked by catalase. The enzymatic destruction of glycocalyx, lining the surface of endothelial cells, significantly weakens the bloodstream-induced shear vasodilation (Kvietys and Granger 2012). Thus, the pharmacological stabilization of the microfilament / microtubule network of the endotheli-al cytoskeleton can contribute to vasodilation induced by the bloodstream.
NADPH oxidases (NOX) are enzymes that produce reactive oxygen species (ROS) and are involved in the pathogenesis of a number of endothelium-associated diseases, such as hypertension and stroke (Drummond and Sobey 2015).
An interesting fact is that studies have shown a decrease in the level of NO and an increase in the activity of arginase under the action of NOX2, which directly indicates the participation of NOX2 in the pathogenesis of endothelial dysfunction. Inhibition of NOX2 activity in endothelial cells in mice significantly prevents premature aging of endotheliocytes by limiting an increase in expression and arginase activity (Rojas et al. 2017).
The main source of reactive oxygen species (ROS) in vascular oxidative stress, which is one of the main causes of cardiovascular diseases, is NOX1 and NOX2 oxidases (Drummond et al. 2011). These NADPH^H oxidase isoforms are expressed by endothelial cells, and a balanced decrease in their activity with the help of selective inhibitors can be a rational approach to the therapy, including that of endothelial dysfunction. Vessel walls are exposed to direct destruction under the action
of excess ROS, which trigger a number of redox-sensi-tive transcriptional pathways (Drummond et al. 2011). Low-density lipoproteins (LDL) are trapped and oxidized in the vascular endothelium, and the oxidized form of LDL causes further oxidative stress in endothe-lial cells, smooth muscle cells, and foamy cells, which aggravates atherogenesis. ROSs produced in the vessel wall are highly reactive particles and do not force stable by-products into the bloodstream, which complicates the diagnosis of atherogenesis (Lee et al. 2012). Studies on the role of NADPH-H oxidases in endothelial homeo-stasis provide strong evidence that pharmacological inhibitors of this enzyme can be used as agents for the treatment of oxidative stress and vascular pathologies associated with it. Some inhibitors with an established NADPH-oxidase inhibitory activity are presented in Table 2 (Drummond et al. 2011).
Recently, a group of scientists developed and synthesized new photoactivatable analogs of NADPH. These compounds have one or two carboxymethyl groups at the 2'- and / and 3'-positions of the ribose in the adenosine fragment instead of the 2'-phosphate group and differ in nature by the electron donor in their photoacti-vatable chromophore (replacing the nicotinamide fragment). The dependence of eNOS on the formation of photoinduced NO was blocked using two NOS inhibitors (NS1 and L-NAME) aimed at the reductase and ox-ygenase domains, respectively. It has been established that two compounds that have one carboxymethyl group at the 3'-position of the ribose colocalize with the help of the Golgi apparatus (the main intracellular location of eNOS) and demonstrate a high intracellu-lar two-photon brightness. In addition, eNOS-depend-ent photo-oxidation was observed only for these two compounds, which is accompanied by a significant in-tracellular production of NO, which takes into account specific photo-cytotoxic effects. Thus, it is obvious that effective photoactivatable NADPH analogues targeting NOS can have important consequences for the generation of apoptosis in tumor cells or the modulation of NO-dependent physiological processes. Studies have also shown a role of a number of naturally occurring phenolic compounds, such as berberine, timoquinone, catechin, celastrol, apocynin, resveratrol, curcumin, hesperidin, G-hesperidin and quercetin in the inhibition of NOX (Yousefian et al. 2019).
NOX1 and NOX2 oxidases appear to be the main causes of vascular oxidative stress in cardiovascular diseases, which makes them promising targets; however, a rational development of highly selective inhibitors of these isoforms is required. NOX2 oxidase plays a decisive role in oxidative stress and vascular dysfunction caused by insulin resistance (Sukumar et al. 2013). Acute and chronic inhibition of NOX2 with the 18-ami-no acid peptide gp91ds-tat causes the restoration of vasomotor function and a decrease in oxidative stress in animal models of insulin resistance (Sukumar et al. 2013). In transgenic mice with endothelium insulin re-
sistance and the deleted NOX2 genome, superoxide anion formation reduced and the vascular function improved, which also indicates the involvement of NOX2 oxidase in the pathogenesis of diabetic endothelial dysfunction (Sukumar et al. 2013). The activation of NOX2 oxidase was documented and confirmed in neurovascu-lar endothelium and neurons in such neurodegenerative diseases,as mild cognitive impairment, Parkinsons disease, and Alzheimer's disease (Zhang et al. 2001). The survival rate of neurons is significantly reduced in the presence of p-amyloid, but the toxic effect of the latter is weakened in the presence of apocynin, which is a NOX2 inhibitor (Cahill-Smith and Li 2014). NADPH oxidases are also considered as therapeutic targets for new treatments for ischemic stroke, often accompanied by endothelial dysfunction of cerebral vessels (McCann and Roulston 2013). Such inhibitors of NOX2 oxidase, such as apocynin, diphenylene iodonium, gp91ds-tat, VAS2870 (Table 1) showed promising results in reducing damage and restoring ischemia-exposed laboratory animals (McCann and Roulston 2013).
The role of ACE2 in the pharmacological correction of endothelial dysfunction
The next molecular target, the pharmacological effect on which can lead to an improvement in endothelial dysfunction, is agiotensin-converting enzyme 2 (ACE2). ACE2 catalyzes the transformation of peptides Ang I and Ang II into shorter peptides Ang-(1-9) and Ang-(1-7).
Numerous data suggest that the renin-angiotensin system (RAS) is the most important regulator of cardiovascular homeostasis and plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis (Zhang et al. 2015).
The low content of Ang-(1-7), caused by deactivation of ACE2, leads to vascular damage in hypertension, diabetes, atherosclerosis and kidney disease (Montezano et al. 2014). The effect of the low-molecular-weight compound XNT, which activates ACE2, on the endothelial function was studied in spontaneously hypertensive and diabetic rats (Fraga-Silva et al. 2013). The vasodilator responses of the aorta of the laboratory animals to acetyl-choline and sodium nitroprusside increased significantly in XNT-treated (1 mg/kg per day for 4 weeks) animals with both pathologies; also a decrease in the level of ROS in the aorta was recorded (Fraga-Silva et al. 2013).
Currently, it has been demonstrated that overexpression of ACE2 and Ang-(1-7) protects the function of en-dothelial cells and inhibits atherosclerotic evolution. The mechanism of protection of endothelial cells and the anti-atherosclerotic action of ACE2 and Ang-(1-7) is due to the counterregulation of Ang II signaling, the inhibition of the inflammatory response and an increase in the ability of the antioxidant (Zhang et al. 2015).
Table 1. Clinical studies of drugs that resulted in improved endothelial dysfunction.
Pathological condition
Medicinal product
Structural formula
Main pharmacological effects
Chronic heart failure
Rosuvastatin (lipid-lowering drug of IV generation from the group of statins)
Oxidized LDL 4 Lipid peroxidation 4 Stem cells and progenitor
cells t POR t (Erbs et al. 2011) EDVD t Apoptosis 4 SOD t MDA 4 (Geng et al. 2019, Radenkovic et al. 2013)
Acute coronary syndrome
Perindopril (angiotensin converting enzyme (ACE) inhibitor)
Apoptosis 4 CD34 + mobilization f VEGF Î TNF-a 4 Bradykinin f Angiotensin 2 4 eNOS mRNA f (Cangiano et al. 2011)
Cardiac syndrome X
Nebivolol (cardioselective beta-blocker of III generation with vasodilating properties)
FMD High sensitivity to C-reactive protein 4 Factor von Willebrand 4 Fibrinogen 4 MDA 4 EDVD f (Borghi et al. 2017)
Hypertensive left ventricular hypertrophy
Carvedilol (alpha and beta-blocker without internal sympathomimetic activity)
FMD f Endothelin-1 4 NO f
(Xiaozhen et al. 2010) ENVD f (Peller et al. 2015)
Coronary heart disease and impaired glucose tolerance
Pioglitazone (selective stimulant of PPAR-y receptors and, to a lesser extent, of PPAR-a receptors)
FMD f TNF-a 4 Triglycerides 4 high molecular weight adiponectin f (Rizza et al. 2011)
Hypertension and impaired glucose tolerance / Peripheral artery disease
Telmisartan (angiotensin II receptor antagonist)
FMD Î Insulin resistance 4 Glucose Tolerance f (Perl et al. 2010) P38 MAPK NO f Angiotensin 2 4 (Radenkovic et al. 2013) Maximum walking distance f
FMD f (Zankl et al. 2010)
Pathological condition Medicinal product Structural formula Main pharmacological effects
Type 2 diabetes Gliclazide (insulin secretion stimulator by pancreatic beta cells) FMD T Endothelial progenitor cells T (Chen et al. 2011) IL-6 4 ICAM-1 4 E-selectin 4 (Erem et al. 2014)
Obesity Pitavastatin (HMG-CoA reductase inhibitor) FMD T Triglycerides T (Nagashima and Endo 2011) Apoptosis 4 NO T PGE2 4 eNOS T (Haybar et al. 2019)
Behcet's disease Atorvastatin (selective competitive inhibitor of HMG-CoA reductase)
Behcet's disease Lisinopril (an ACE inhibitor of prolonged action) FMD T (Inanc et al. 2010) Apoptosis 4 CD34 + mobilization T TNF-a 4 Bradykinin T Angiotensin 2 4 (Cangiano et al. 2010)
Polycystic ovary syndrome Spironolactone (potassium-sparing diuretic, competitive antagonist of aldosterone and other mineralocorticoids) FMD T (Bajuk et al. 2011) Icam-1 ROS 4 eNOS T (Dutzmann et al. 2014)
Subclinical hypothyroidism Levothyroxine POR T FT4 T TSH 4 Total cholesterol 4
Ankylosing spondylitis Infliximab (monoclonal antibodies to TNF-a) - FMD T Serum nitrite 4 Erythrocyte sedimentation rate 4 C-reactive protein 4 (Syngle et al. 2010)
Chronic hemodialysis Simvastatin (active metabolite inhibits HMG-CoA reductase) FMD T Oxidized LDL 4 VCAM-1 4 8-epi-prostagandin F2 4 NO bioavailability (Kishimoto et al. 2019)
Note: LDL - low-density lipoproteins; SOD - superoxide dismutase; MDA - malonic dialdehyde; FMD - flow-mediated dilatation; VEGF - Vascular endothelial growth factor; TNF-a - tumor necrosis factor -a; TSH - thyroid-stimulating hormone; VCAM-1 - vascular cell adhesion molecule 1; ROS - reactive oxygen species; eNOS - endothelial nitric oxide synthase.
Table 2. NADPH inhibitors^H-oxidases (26).
Name Structural formula Mechanism of action related to NADP^H-oxidase Other pharmacological effects
4- (2-aminoethyl) benzenesulfonylfluoride HCl O F Oxidase assembly inhibitor: inhibits the association of the NOX2 subunit and p47phox. Does not remove O2" generated in systems that do not contain cells Non-selective serine protease inhibitor
Apocynin YO Oxidase assembly inhibitor: inhibits the association of p47phox and membrane-bound heterodimer H2O2 absorber
Diphenyleneiodonium Flavoprotein inhibitor Inhibitor of NADP№H-ubiquinone oxidoreductase, NADPH •H-dehydrogenase, xanthine oxidase, cytochrome-p450 oxidoreductase, NOS and bacterial nicotine oxidase
GK-136901 The claimed inhibitor of NOX1 and NOX4 oxidases. The mechanism of action is not established, but the structural similarity with NADP^H implies competitive substrate inhibition
ML171 h^ Selective inhibitor of NOX1 oxidase (IC50 0.25 ^M) compared with other isoforms of NADPH-H oxidases (IC50>3 ^M). Does not absorb ROS generated by xanthine oxidase
Nox2ds-tat (H)-RKKRRQRRRCSTRIRRQL-NH2 Oxidase assembly inhibitor: inhibits the association of the NOX2 subunit and p47phox. Does not remove O2" generated in systems that do not contain cells
Plumbagin o Inhibits the NADPH-dependent O2" formation in various cell lines expressing NOX4 oxidase; mechanism of action is unknown Chemical structure can provide an ROS-absorbing effect.
PR-39 RRRPRPPYLPRPRPPPFFPPRLPPRIPPG FPPRFPPRFP Binds to the SH3 domains of the p47phox subunit and prevents binding to the p22phox subunit Appears to bind to other proteins containing SH3 domains.
S17834 L ^.0CH3 Alleged direct inhibitor of NADPH oxidase, but the mechanism of action is not established.
Name Structural formula Mechanism of action related to NADP^H-oxidase Other pharmacological effects
VAS2870 Unidentified action mechanism, does not bind o/-
VAS3947 Reduces ROS produced by NADPH-oxidase, has micromolar activity, regardless of the isoform, does not inhibit the formation of ROS by xanthine oxidase and eNOS activity
Note: eNOS - endothelial NO synthase; SH3 - Src homologous 3 domain.
Arginase II is a promising target for the creation of drugs aimed at the pharmacological correction of endothelium-associated pathology
The decrease in the bioavailability of NO, leading to endothelial dysfunction, can be caused by competition between endothelial NO synthase (eNOS) and arginase for a common substrate - L-arginine. The expression of argi-nase and its activity is increased in many cardiovascular diseases, including ischemic-reperfusion injuries, hypertension, atherosclerosis, and diabetes (Rabelo et al. 2015, Shakhno et al 2017).
The studies conducted have provided evidence of the role of Arg-I in promoting endothelial cell aging, confirming that activation of both Arg-I and Arg-II have similar functions of inducing the uncoupling of eNOS from the substrate. The molecular basis for the existing subtle difference between Arg-I and Arg-II is yet to be further studied.
Arginase contributes to microvascular endothelial dysfunction in obesity. Its effect decreases with age due to a higher level of vascular oxidative stress. Obesity is accompanied by accelerated microvascular remodeling, the extent of which is related to the amount of arginase in the vascular wall (Masi et al. 2018).
In endothelial cells, arginase isoform II prevails. The structure of both human arginase isoforms was studied using an X-ray structural analysis, which made it possible to identify a binuclear manganese cluster in the active site of enzymes and the identical structure of the active sites. In the active site of the enzyme, ornithine and urea are formed as a result of the breakdown of the tetrahe-dral intermediate formed by adding a hydroxide anion coordinated by manganese ions to the guanidine group of arginine. The breakthrough step in the development of arginase inhibitors was the discovery of 2-(S)-amino-6-bo-ronohexanoic acid (ABH) (Masi et al. 2018). A fragment of boronic acid ABH undergoes a nucleophilic attack by a hydroxide anion, as a result of which a tetrahedral bo-ronate anion is formed, resembling an intermediate, resulting in the cleavage of arginine. The rational design of stronger inhibitors led to the understanding that substit-
uents can be introduced into the a-position of the amino acid fragment, providing for additional interactions with arginase. The result of this work was the production of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl) ethyl) hexa-noic acid (1) (Fig. 1), which has sub-micromolar activity with respect to human arginase I and II (Van Zandt et al. 2013). Inhibitor 1 was also investigated in the in vivo model of myocardial ischemia / reperfusion injury and showed a significant reduction in the area of infarction (Van Zandt et al. 2013). It should be noted that the enan-tiomer of compound 1, which is distinguished by the absolute configuration of the stereogenic center, has neither an inhibitory activity against arginase, nor a therapeutic effect in myocardial ischemia.
The introduction of the piperidine and tropan fragments into the a-position of the ABH amino acid fragment resulted in arginase inhibitors 2 and 3, respectively (Fig. 1), having a nanomolar activity against human arginase (Golebiowski et al. 2013). Correction of endothelial dysfunction caused by obesity was achieved by introducing the inhibitor of arginase Nm-hydroxy-nor-L-arginine (nor-NOHA) into the diet of the studied rats (Chung et al. 2014). In this case, a significant increase in the expression of eNOS and in the level of NO and a significant decrease in the content of the intercellular adhesion molecule 1 (ICAM-1) in plasma were recorded (Chung et al. 2014). Despite the curative effects of arginase inhibitors, its presence in macrophages should be taken into account, as it may entail inflammatory and other undesirable effects on the vessels and some organs (Steppan et al. 2013).
The possible role of the regulatory enzyme GSNO reductase (GSNOR) in the pharmacological correction of endothelial dysfunction
One of the main organs dependent on GSNOR is the heart and its surrounding vascular system. GSNOR is an attractive therapeutic goal. Inhibition of GSNOR increases the availa-
Figure 1. Structural formulas of arginase inhibitors, developed using rational design.
bility of NO in the cell and, in turn, normalizes NO-mediated signaling pathways. (Cahill-Smith and Li 2014)
One of the physiological forms of NO is S-nitrosoglu-tathione (GSNO) of cytoplasm. GSNO catabolism with the help of the GSNO reductase regulatory enzyme (GSNOR) reduces the amount of GSNO in vivo, which leads to an influence on the processes involving NO, including vasodilatation. The endothelial function was studied under the conditions of inhibiting GSNOR, and the vasodilating effect of the GSNOR inhibitor N6338 was established (Chen et al. 2014). In hypertensive rats, oral administration of N6338 for 14 days reduced blood pressure and vascular resistance index, and restored the initially impaired flow-mediated vasodilation to the level of the normal animals. There was no chemical formula of N6338 in either (Chen et al. 2014), or in cross references.
In addition, dozens of small molecules were identified that can inhibit GSNOR to varying degrees (Green et al. 2012, Jiang et al. 2016).
Two of them, N6022 (3-(5-(4-(1H-imidazol-1-yl) phe-nyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl) propionic acid) and N91115 from Nivalis Therapeutics (USA) are promising as potentially safe and effective GSNOR inhibitors that have been clinically tested for the treatment of asthma (clinictrials.gov - NCT01316315) and cystic fibrosis. In mice, it has been demonstrated that the ILD compound SPL-334 functions as a prophylactic and therapeutic agent for attenuating profibrotic cytokines and the accumulation of collagen in the lungs.
Thus, GSNOR can also be considered as a target for drugs that improve endothelial dysfunction.
Conclusion
From an enzymological point of view, NOS has a number of unique properties: NOS is the most regulated enzyme in biology. This is the only known enzyme that has 5 co-factors. As a result, the system, the generation of nitric oxide is the most sensitive system that responds to many changes that occur in the body.
The most recent studies showing the ubiquitous localization of arginase I and II make it possible not to dwell on this differentiation and not to mark any significant distinction between selective and non-selective inhibitors. In addition, all arginase inhibitors are divided into specific, acting directly on the enzyme itself and blocking its active center, and non-specific, acting on the enzyme indirectly.
NOX1 and NOX2 oxidases, as NADP^H oxidase iso-forms, expressed by endothelial cells, agiotensin-convert-ing enzyme 2 and GSNO reductase may be of interest in a targeted search for drugs for the pharmacological correction of endothelial dysfunction.
Conflicts of Interest
The authors have no conflict of interest to declare.
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Contribution of authors
■ Liliya V. Korokina, PhD, Associate Professor, Department of Pharmacology and Clinical Pharmacology; e-mail: [email protected]. The author analyzed publications on modern research in the field of pharmacological correction of endothelial dysfunction, possible approaches to the search for new pharmacological targets and took part in the systematization and generalization of the material for the article.
■ Ivan V. Golubev, obstetrician-gynecologist; e-mail: [email protected]. The author analyzed the role of NOX1 and NOX2 oxidase in the pharmacological correction of endothelial dysfunction
■ Olga N. Pokopejko, student, Medical Faculty; e-mail: [email protected]. The author conducted an analysis of the role of APF2 in the pharmacological correction of endothelial dysfunction
■ Anastasia V. Zagrebelnaya, postgraduate student, Department of Pharmacology and Clinical Pharmacology; e-mail: [email protected]. The author searched for data on the possible role of the regulatory enzyme GSNO reductase (GSNOR) in the pharmacological correction of endothelial dysfunction.
■ Sergey A. Demchenko, postgraduate student, Department of Pharmacology and Clinical Pharmacology; e-mail: [email protected]. The author analyzed arginase 2 as a target for pharmacological correction of endothelial dysfunction.
