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The pathogenesis of metabolic syndrome (MS) is characterized by obesity, hypertension, dyslipidemia and insulin resistance. MS increases the risk of developing type 2 diabetes mellitus (DM2). The neuronal isoform of nitric oxide synthase (nNOS) is defined by complex protein-protein interactions, since nNOS, unlike other isoforms of NOS,contains a C-terminal PDZ domain, which allows it to conjugate with other proteins and, first of all, to interact with an adapter of neuronal, or type 1, nitric oxide synthase (NOS1AP), also denoted CAPON in our work. Changes in the interaction between nNOS and NOS1AP lead to metabolic disorders in brain, heart, liver and skeletal muscles, which plays a key role in the development of MS and T2DM. NOS1AP, interacting with the PDZ domain of nNOS, competes with the postsynaptic density protein (PSD95) and regulates the stability of subcellular localization of nNOS and enzyme expression during synapse formation. NOS1AP promotes nNOS binding to targets such as small GTPase (Dexras1), synapsines, regulating the formation of dendritic roots, mediates activation of the nNOS-p38MAP kinase pathway during excitotoxicity. It has been shown that single-nucleotide polymorphism of the NOS1AP gene and its overexpression in the myocardium leads to the manifestation of long QT syndrome, which is most clearly manifested in elderly patients with DM2. It was found that the genetic polymorphism of NOS1AP affects insulin secretion when using calcium blockers, and can promote the development of DM2. The functional role of NOS1AP in stabilizing the functions of skeletal muscle nNOS in the cytoskeletal complex associated with dystrophin/utrophin was discovered. The purpose of the review is to provide updated information on the role of NOS1AP and the nNOS/NOS1AP complex in the pathogenesis of MS and DM2. The potential molecular mechanisms of the interaction of NOS1AP with nNOS and with other proteins, which leads to change in nNOS activity, localization and content, are discussed.

This literature review presents the role of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO), as well as arginine, the enzyme substrate, in the disease of metabolic syndrome and COVID-19 (SARS-CoV-2 virus). Metabolic syndrome is a combination of obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension. It has been shown that in elderly people, patients with obesity, metabolic syndrome, type 2 diabetes mellitus (DM2), and patients with COVID-19, endothelial dysfunction (ED) and vascular endothelial activation are detected. ED is the main cause of a number of pathological conditions during the development of COVID-19 and earlier in patients with metabolic syndrome, while a sharp drop in the level of nitric oxide (NO) is detected due to a decrease in the expression and activity of eNO synthase and enzyme depletion, which leads to a violation of the integrity of bloodvessels, that is, to vasoconstrictive, inflammatory and thrombotic conditions, followed by ischemia of organs and edema of tissues. It should be noted that metabolic syndrome, DM2, hypertension and obesity, in particular, are age-related diseases, and it is known that blood glucose levels increase with age, which reduces the bioavailability of NO in endothelial cells. Defects in the metabolism of NO cause dysfunction in the pulmonary blood vessels, the level of NO decreases, which leads to impaired lung function and coagulopathy. The review presents possible mechanisms of these disorders associated with ED, the release of eNO synthase, changes in phosphorylation and regulation of enzyme activity, as well as insulin resistance. A modern view of the role of the polymorphism of the eNO synthase gene in the development of these pathologies is presented. To increase the level of endothelial NO, drugs are offered that regulate the bioavailability of NO. These include arginine, agonist NO – minoxidil, steroid hormones, statins, metformin. However, further research and clinical trials are needed to develop treatment strategies that increase NO levels in the endothelium.

The study of the molecular mechanisms of metabolic syndrome (MS) and its complications are among the most acute problems of modern endocrinology. Functional changes in the expression, activity, and regulatory properties of neuronal NO synthase (nNOS), which catalyzes the formation of the most important secondary mediator, nitric oxide (NO), and its dependent NO/cGMP signaling pathways in the brain, myocardium, and skeletal muscles, play a key role among the molecular causes of MS. In the brain, nNOS is associated with NMDA receptors, the hyperactivation of which in MS leads to excessive stimulation of nNOS and hyperproduction of NO, which leads to NO-induced damage to neurons and disruption of the central regulation of physiological processes and neurodegeneration. In the myocardium with MS, there are changes in the expression and localization of nNOS, as well as its functional interaction with cytoskeletal proteins, which leads to disorders of myocardial contraction and hypertrophy. In skeletal muscles, nNOS controls their contraction, oxidative metabolism, is involved in the regulation of vascular relaxation, and also participates in the regulation of glucose transport. A decrease in the expression and activity of nNOS, as well as dysregulation of its activity in MS, cause disturbances of these processes and make a significant contribution to the development of insulin resistance and deterioration of glucose homeostasis. Thus, nNOS can be considered an important therapeutic target in the treatment of MS and other metabolic disorders, as well as to prevent their complications from the nervous and cardiovascular systems and the musculoskeletal system.