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Human Nitric Oxide Synthase-Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases.

ABSTRACT: In various diseases, there is an increased production of the free radicals needed to carry out certain physiological processes but their excessive amounts can cause oxidative stress and cell damage. Enzymes play a major role in the transformations associated with free radicals. One of them is nitric oxide synthase (NOS), which catalyzes the formation of nitric oxide (NO). This enzyme exists in three forms (NOS1, NOS2, NOS3), each encoded by a different gene. The following work presents the most important information on the NOS isoforms and their role in the human body, including NO synthesis in various tissues and cells, intercellular signaling and activities supporting the immune system and regulating blood vessel functions. The role of NOS in pathological conditions such as obesity, diabetes and heart disease is considered. Attention is also paid to the influence of the polymorphisms of these genes, encoding particular isoforms, on the development of these pathologies and the role of NOS inhibitors in the treatment of patients.

SUBMITTER: Krol M

PROVIDER: S-EPMC7793075 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Human Nitric Oxide Synthase-Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases.

Król Magdalena M Kepinska Marta M

International journal of molecular sciences 20201223 1

In various diseases, there is an increased production of the free radicals needed to carry out certain physiological processes but their excessive amounts can cause oxidative stress and cell damage. Enzymes play a major role in the transformations associated with free radicals. One of them is nitric oxide synthase (NOS), which catalyzes the formation of nitric oxide (NO). This enzyme exists in three forms (NOS1, NOS2, NOS3), each encoded by a different gene. The following work presents the most ...[more]

PMID: 33374571

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Project description:This review describes and summarizes the role of neuronal nitric oxide synthase (nNOS) on the central nervous system, particularly on brain regions such as the ventrolateral medulla (VLM) and the periaqueductal gray matter (PAG), and on blood vessels and the heart that are involved in the regulation and control of the cardiovascular system (CVS). Furthermore, we shall also review the functional aspects of nNOS during several physiological, pathophysiological, and clinical conditions such as exercise, pain, cerebral vascular accidents or stroke and hypertension. For example, during stroke, a cascade of molecular, neurochemical, and cellular changes occur that affect the nervous system as elicited by generation of free radicals and nitric oxide (NO) from vulnerable neurons, peroxide formation, superoxides, apoptosis, and the differential activation of three isoforms of nitric oxide synthases (NOSs), and can exert profound effects on the CVS. Neuronal NOS is one of the three isoforms of NOSs, the others being endothelial (eNOS) and inducible (iNOS) enzymes. Neuronal NOS is a critical homeostatic component of the CVS and plays an important role in regulation of different systems and disease process including nociception. The functional and physiological roles of NO and nNOS are described at the beginning of this review. We also elaborate the structure, gene, domain, and regulation of the nNOS protein. Both inhibitory and excitatory role of nNOS on the sympathetic autonomic nervous system (SANS) and parasympathetic autonomic nervous system (PANS) as mediated via different neurotransmitters/signal transduction processes will be explored, particularly its effects on the CVS. Because the VLM plays a crucial function in cardiovascular homeostatic mechanisms, the neuroanatomy and cardiovascular regulation of the VLM will be discussed in conjunction with the actions of nNOS. Thereafter, we shall discuss the up-to-date developments that are related to the interaction between nNOS and cardiovascular diseases such as hypertension and stroke. Finally, we shall focus on the role of nNOS, particularly within the PAG in cardiovascular regulation and neurotransmission during different types of pain stimulus. Overall, this review focuses on our current understanding of the nNOS protein, and provides further insights on how nNOS modulates, regulates, and controls cardiovascular function during both physiological activity such as exercise, and pathophysiological conditions such as stroke and hypertension.

Project description:Nitric oxide (NO), which is produced from L-arginine by the nitric oxide synthase (NOS) family of enzymes, is an important second-messenger molecule that regulates several physiological functions. In endothelial cells, it relaxes smooth muscle, which decreases blood pressure. Macrophage cells produce NO as an immune defense system to destroy pathogens and microorganisms. In neuronal cells, NO controls the release of neurotransmitters and is involved in synaptogenesis, synaptic plasticity, memory function, and neuroendocrine secretion. NO is a free radical that is commonly thought to contribute to oxidative damage and molecule and tissue destruction, and thus it is somewhat surprising that it has so many significant beneficial physiological effects. However, the cell is generally protected from NO's toxic effects, except under certain pathological conditions in which excessive NO is produced. In that case, tissue damage and oxidative stress can result, leading to a wide variety of diseases, including rheumatoid arthritis, Alzheimer's disease, and Parkinson's disease, among others. In this Account, we describe research aimed at identifying small molecules that can selectively inhibit only the neuronal isozyme of NOS, nNOS. By targeting only nNOS, we attained the beneficial effects of lowering excess NO in the brain without the detrimental effects of inhibition of the two isozymes found elsewhere in the body (eNOS and iNOS). Initially, in pursuit of this goal, we sought to identify differences in the second sphere of amino acids in the active site of the isozymes. From this study, the first class of dual nNOS-selective inhibitors was identified. The moieties important for selectivity in the best lead compound were determined by structure modification. Enhancement provided highly potent, nNOS-selective dipeptide amides and peptidomimetics, which were active in a rabbit model for fetal neurodegeneration. Crystal structures of these compounds bound to NOS isozymes showed a one-amino-acid difference between nNOS and eNOS in the second sphere of amino acids; this was the difference that we were searching for from the beginning of this project. With the aid of these crystal structures, we developed a new fragment-based de novo design method called "fragment hopping", which allowed the design of a new class of nonpeptide nNOS-selective inhibitors. These compounds were modified to give low nanomolar, highly dual-selective nNOS inhibitors, which we recently showed are active in a rabbit model for the prevention of neurobehavioral symptoms of cerebral palsy. These compounds could also have general application in other neurodegenerative diseases for which excess NO is responsible.

Dataset Information

Human Nitric Oxide Synthase-Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases.

Publications

Human Nitric Oxide Synthase-Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases.

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