Nitric oxide signaling in health and disease

Cell, Год журнала: 2022, Номер 185(16), С. 2853 - 2878

Опубликована: Авг. 1, 2022

The surprising discovery that the diatomic gas nitric oxide (NO) is generated by mammalian cells and serves to regulate a multitude of physiological processes has continued fascinate biologists for almost four decades. biochemistry NO complex, novel insights into control biosynthesis mechanisms signal transduction are continuously emerging. key regulator cardiovascular function, metabolism, neurotransmission, immunity, more, aberrant signaling central feature many major disorders including disease, diabetes, cancer. Here, we discuss basics biology emphasizing recent advances in field means increasing bioactivity with therapeutic nutritional implications.

Язык: Английский

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Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(13), С. 3294 - 3294

Опубликована: Июль 4, 2019

The maintenance of physiological levels nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to activation iNOS under different stress conditions, leads dysfunction and, in late stages, development atherosclerosis. Oxidized LDLs (oxLDLs) represent major candidates trigger biomolecular processes accompanying and inflammation leading atherosclerosis, though pathophysiological mechanism still remains be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment modulation eNOS/iNOS machinery, downregulating via HMGB1-TLR4-Caveolin-1 pathway. increased lead sustained scavenger receptor LOX-1 subsequently, NFkB activation, which, turn, increases iNOS, EC oxidative stress. Finally, these events are associated with reduced protective autophagic response accelerated apoptotic death, which activates atherosclerotic development. Taken together, this information sheds new light on mechanisms oxLDL-related functionality opens perspectives atherothrombosis prevention.

Язык: Английский

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Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration

Nature Neuroscience, Год журнала: 2020, Номер 23(9), С. 1079 - 1089

Опубликована: Авг. 10, 2020

Язык: Английский

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Human skeletal muscle nitrate store: influence of dietary nitrate supplementation and exercise

The Journal of Physiology, Год журнала: 2019, Номер 597(23), С. 5565 - 5576

Опубликована: Июль 27, 2019

Key points Nitric oxide (NO), a potent vasodilator and regulator of many physiological processes, is produced in mammals both enzymatically by reduction nitrite nitrate ions. We have previously reported that, rodents, skeletal muscle serves as reservoir, with levels greatly exceeding those blood or other internal organs, being reduced to NO during exercise. In the current study, we show that concentration substantially greater than elevated further dietary ingestion human volunteers. also high‐intensity exercise results store following supplementation, likely consequence its NO. report presence sialin, transporter, xanthine oxidoreductase muscle, indicating has necessary apparatus for transport, storage metabolism. Abstract Rodent contains large can be augmented consumption nitrate. This reservoir been found an important source nitric (NO) via tissue oxidoreductase. To explore if this pathway active exercise, it sensitive local availability, assessed exercise‐induced changes concentrations young healthy humans, under baseline conditions consumption. were far higher plasma (∼4‐fold ∼29‐fold, respectively), single bolus (12.8 mmol) significantly (∼19‐fold) (∼5‐fold). Consistent these observations, previous suggestions present western blot data significant expression nitrate/nitrite transporter sialin muscle. Furthermore, (by ∼39%), but only increased store. Our indicate stores are intake may contribute generation Together, findings suggest plays role metabolism humans.

Язык: Английский

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Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease

British Journal of Pharmacology, Год журнала: 2019, Номер 177(24), С. 5467 - 5488

Опубликована: Ноя. 13, 2019

PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects NO/cGMP signalling in tissues through inhibition cGMP degradation. Although these agents were originally developed for treatment hypertension angina, unanticipated side led advances erectile dysfunction and, later, pulmonary arterial hypertension. In last decade, accumulating evidence suggests that PDE5Is may confer wider range clinical benefits than was previously recognised. This has broader interest cardiovascular therapeutic potential PDE5Is, conditions hypertension, myocardial infarction, stroke, peripheral disease, chronic kidney disease diabetes mellitus. Here, we review pharmacological properties established licensed uses this drug, along with emerging developments possible future indications.

Язык: Английский

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NO as a multimodal transmitter in the brain: discovery and current status

British Journal of Pharmacology, Год журнала: 2018, Номер 176(2), С. 197 - 211

Опубликована: Ноя. 7, 2018

NO operates throughout the brain as an intercellular messenger, initiating its varied physiological effects by activating specialized GC‐coupled receptors, resulting in formation of cGMP. In line with widespread expression this pathway, participates numerous different functions. This review gives account discovery a signalling molecule brain, experiments that originated search for mysterious cGMP‐stimulating factor released from central neurones when their NMDA receptors were stimulated, and summarizes subsequent key steps helped establish status transmitter. Currently, various modes operation are viewed to underlie diverse behaviour, ranging very local between synaptic partners (in orthograde or retrograde directions) volume‐type transmission whereby synthesized multiple synchronous sources summate spatially temporally influence intermingled neuronal non‐neuronal cells, irrespective anatomical connectivity. Linked Articles article is part themed section on Nitric Oxide 20 Years 1998 Nobel Prize. To view other articles visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc

Язык: Английский

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Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors

Biology, Год журнала: 2021, Номер 10(10), С. 1041 - 1041

Опубликована: Окт. 14, 2021

Cardiovascular diseases include all types of disorders related to the heart or blood vessels. High pressure is an important risk factor for cardiac complications and pathological disorders. An increase in circulating angiotensin-II a potent stimulus expression reactive oxygen species pro-inflammatory cytokines that activate oxidative stress, perpetuating deleterious effect hypertension. Studies demonstrate capacity NO prevent platelet leukocyte activation adhesion inhibition proliferation, as well modulate inflammatory anti-inflammatory reactions migration vascular smooth muscle cells. However, conditions low availability NO, such during hypertension, these processes are impaired. Currently, there great interest development compounds capable releasing modulated stable way. Accordingly, containing metal ions coupled being investigated widely recognized having relevance treatment different diseases. Therefore, exogenous administration attractive pharmacological alternative study The present review summarizes role nitric oxide focusing on new donors, particularly metal-based drugs their protagonist activity function.

Язык: Английский

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Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health

Stroke, Год журнала: 2023, Номер 54(3), С. 686 - 696

Опубликована: Фев. 27, 2023

eNOS (endothelial nitric oxide synthase) is critically important enzyme responsible for regulation of cardiovascular homeostasis. Under physiological conditions, constitutive activity and production endothelial (NO) exert essential neurovascular protective functions. In this review, we first discuss the roles NO in prevention neuronal amyloid accumulation formation neurofibrillary tangles, hallmarks Alzheimer disease pathology. Next, review existing evidence suggesting that released from endothelium prevents activation microglia, stimulates glycolysis astrocytes, increases biogenesis mitochondria. We also address major risk factors cognitive impairment including aging ApoE4 (apolipoprotein 4) genotype with focus on their detrimental effects eNOS/NO signaling. Relevant to recent studies suggested aged heterozygous mice are unique model spontaneous cerebral small vessel disease. regard, contribution dysfunctional deposition Aβ (amyloid-β) into blood wall leading development angiopathy. conclude dysfunction manifested by loss functions may significantly contribute impairment.

Язык: Английский

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Hydrogen Sulfide (H2S)/Polysulfides (H2Sn) Signalling and TRPA1 Channels Modification on Sulfur Metabolism

Biomolecules, Год журнала: 2024, Номер 14(1), С. 129 - 129

Опубликована: Янв. 19, 2024

Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, energy formation. H2Sn, which have additional sulfur atoms to H2S, other S-sulfurated such cysteine persulfide residues of proteins, are including 3-mercaptopyruvate sulfurtransferase (3MST). H2Sn also generated the chemical interaction H2S with NO, or lesser extent H2O2. S-sulfuration (S-sulfhydration) has been proposed mode action regulate activity target molecules. Recently, we found that H2S/H2S2 release neurotransmitters, GABA, glutamate, D-serine, co-agonist N-methyl-D-aspartate (NMDA) receptors. facilitates induction hippocampal long-term potentiation, synaptic model memory formation, enhancing NMDA receptors, while H2S2 achieves this activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading activation nearby neurons. The recent findings show aspects TRPA1 channels—that is, regulation levels sulfur-containing their metabolizing enzymes. Disturbance H2S/H2Sn demonstrated be involved various diseases, cognitive psychiatric diseases. physiological pathophysiological roles these will discussed.

Язык: Английский

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Sympathetic Activation in Hypertension: Importance of the Central Nervous System

American Journal of Hypertension, Год журнала: 2020, Номер 33(10), С. 914 - 926

Опубликована: Май 1, 2020

Abstract The sympathetic nervous system plays a critical role in the pathogenesis of hypertension. central (CNS) organizes outflow and various inputs from periphery. brain renin–angiotensin has been studied regions involved controlling outflow. Recent progress cardiovascular research, particularly vascular biology neuroscience, as well traditional physiological approaches, advanced field neural control hypertension which CNS vital role. Cardiovascular research relating to focused on roles nitric oxide, oxidative stress, inflammation, immunity, network among organs, including heart, kidney, spleen, gut, vasculature. mechanisms are similarly networked with these factors widely neuroscience. In this review, I describe development conceptual flow basis several important original articles discuss potential future breakthroughs leading clinical precision medicine.

Язык: Английский

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