The superoxide radical switch in the biology of nitric oxide and peroxynitrite

Physiological Reviews, Год журнала: 2022, Номер 102(4), С. 1881 - 1906

Опубликована: Май 23, 2022

The free radical nitric oxide ( · NO) is a key mediator in different physiological processes such as vasodilation, neurotransmission, inflammation, and cellular immune responses, thus preserving its bioavailability essential. In several disease conditions, superoxide (O 2 ·− ) production increases leads to the rapid “inactivation” of NO by diffusion-controlled termination reaction that yields potent short-lived oxidant, peroxynitrite. This not only limits for signal transduction but also can divert switch biochemistry toward nitrooxidative processes. Indeed, since early 1990s peroxynitrite (and secondary derived species) has been linked establishment progression acute chronic human diseases normal aging process. Here, we revisit an earlier classical review on role physiology pathology (Pacher P, Beckman J, Liaudet L. Physiol Rev 87: 315–424, 2007) further integrate, update, interpret accumulated evidence over 30 years research. Innovative tools approaches detection, quantitation, sub- or extracellular mapping products (e.g., protein 3-nitrotyrosine) have allowed us unambiguously connect complex with numerous biological outcomes at pathological levels. Furthermore, our current knowledge NO/O interplay cell, tissue, organ levels assisting discovery therapeutic interventions variety diseases.

Язык: Английский

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Oxidative Stress in Healthy and Pathological Red Blood Cells

Biomolecules, Год журнала: 2023, Номер 13(8), С. 1262 - 1262

Опубликована: Авг. 18, 2023

Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, production red blood cells (RBCs). These can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) antioxidant defense mechanisms, plays significant role in pathophysiology diseases. In this review, we discuss most relevant oxidant involved RBC damage, enzymatic low molecular weight systems protect RBCs against oxidative injury, finally, stress different diseases, sickle disease, glucose 6-phosphate dehydrogenase deficiency, pyruvate kinase highlighting underlying mechanisms leading pathological phenotypes.

Язык: Английский

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Mechanisms of pulmonary vascular dysfunction in pulmonary hypertension and implications for novel therapies

AJP Heart and Circulatory Physiology, Год журнала: 2022, Номер 322(5), С. H702 - H724

Опубликована: Фев. 25, 2022

Pulmonary hypertension (PH) is a serious disease characterized by various degrees of pulmonary vasoconstriction and progressive fibroproliferative remodeling inflammation the arterioles that lead to increased vascular resistance, right ventricular hypertrophy, failure. tone regulated balance between vasoconstrictor vasodilator mediators, shift in this an important component PH pathology, Therefore, mainstay current pharmacological therapies centers on vasodilation methodologies either enhance mechanisms such as NO-cGMP prostacyclin-cAMP pathways and/or inhibit endothelin-1, cytosolic Ca

Язык: Английский

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Novel Smooth Muscle Ca ²⁺ -Signaling Nanodomains in Blood Pressure Regulation

Circulation, Год журнала: 2022, Номер 146(7), С. 548 - 564

Опубликована: Авг. 15, 2022

Ca2+ signals in smooth muscle cells (SMCs) contribute to vascular resistance and control blood pressure. Increased hypertension has been attributed impaired SMC signaling mechanisms. In this regard, transient receptor potential vanilloid 4 (TRPV4SMC) ion channels are a crucial entry pathway SMCs. However, their role pressure regulation not identified.We used SMC-specific TRPV4-/- (TRPV4SMC-/-) mice assess the of TRPV4SMC regulation. We determined contribution constrictor effect α1 adrenergic (α1AR) stimulation elevated intraluminal pressure: 2 main physiologic stimuli that constrict resistance-sized arteries. The spatially separated channel subpopulations was evaluated angiotensin II-infused patients with hypertension.We provide first evidence activity elevates resting normal mice. α1AR activated through PKCα (protein kinase Cα) signaling, which contributed significantly vasoconstriction elevation. Intraluminal pressure-induced opposed activation Ca2+-sensitive K+ (BK) channels, indicating functionally opposite pools channels. Superresolution imaging SMCs revealed α1AR:TRPV4 TRPV4:BK nanodomains These data suggest α1AR-TRPV4SMC pressure-TRPV4SMC-BK have effects on pressure, dominating under conditions. Furthermore, mouse model hypertension, α1AR-PKCα-TRPV4 upregulated, whereas dilator pressure-TRPV4-BK disrupted, thereby increasing elevating pressure.Our identify novel Ca2+-signaling regulate demonstrate impairment hypertension.

Язык: Английский

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Oxidative Stress and Cerebral Vascular Tone: The Role of Reactive Oxygen and Nitrogen Species

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 3007 - 3007

Опубликована: Март 5, 2024

The brain’s unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, nitrogen (RNS) and antioxidant defense mechanisms. This review explores the factors contributing vascular tone’s vulnerability in presence of damage, can be clinical interest critically ill patients or those presenting acute brain injuries. high metabolic rate inefficient electron transport chain mitochondria lead significant ROS generation. Moreover, non-replicating neuronal cells low repair capacity increase susceptibility insult. influence cerebral tone permeability, potentially impacting autoregulation. Different species, including superoxide hydrogen peroxide, exhibit vasodilatory vasoconstrictive effects on blood vessels. RNS, particularly NO peroxynitrite, also exert vasoactive effects. further investigates neuroprotective antioxidants, dismutase (SOD), vitamin C, E, glutathione redox system. Various studies suggest that these antioxidants could used as adjunct therapies protect under conditions stress. Nevertheless, more extensive research is required comprehensively grasp relationship stress cerebrovascular tone, explore potential benefits adjunctive critical illnesses

Язык: Английский

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Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(13)

Опубликована: Май 21, 2024

Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an anti-inflammatory phenotype. High stress also induces flow-aligned cell elongation front-rear polarity, but whether these required for phenotype is unclear. Here, we showed that Caveolin-1-rich microdomains polarize downstream end of ECs continuous flow. These were characterized by membrane rigidity, filamentous actin (F-actin), raft-associated lipids. Transient receptor potential vanilloid-type 4 (TRPV4) ion channels ubiquitously expressed on plasma mediated localized Ca2+ entry only at where they physically interacted with clustered Caveolin-1. focal bursts activated endothelial nitric oxide synthase (eNOS) within confines domains. Importantly, found signaling domains both body sustained Finally, TRPV4 was necessary sufficient suppress inflammatory gene expression, exogenous activation ameliorated response stimuli vitro vivo. Our work revealed a polarized mechanosensitive hub arterial dampens expression promotes resilience.

Язык: Английский

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Peroxynitrite: a multifaceted oxidizing and nitrating metabolite

Current Opinion in Chemical Biology, Год журнала: 2024, Номер 80, С. 102459 - 102459

Опубликована: Май 8, 2024

Язык: Английский

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Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies

MedComm, Год журнала: 2025, Номер 6(3)

Опубликована: Март 1, 2025

Pulmonary hypertension (PH) stands as a tumor paradigm cardiovascular disease marked by hyperproliferation of cells and vascular remodeling, culminating in heart failure. Complex genetic epigenetic mechanisms collectively contribute to the disruption pulmonary homeostasis. In recent years, advancements research technology have identified numerous gene deletions mutations, addition bone morphogenetic protein receptor type 2, that are closely associated with remodeling process PH. Additionally, modifications such RNA methylation, DNA histone modification, noncoding RNAs been shown precisely regulate PH molecular networks cell-type-specific manner, emerging potential biomarkers therapeutic targets. This review summarizes analyzes roles currently genes factors PH, emphasizing pivotal role long ncRNAs its regulation. it examines current clinical preclinical therapies for targeting these explores new treatment strategies.

Язык: Английский

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Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(18), С. 9821 - 9821

Опубликована: Сен. 10, 2021

An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. aberrant elevation can indeed lead severe disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce signals regulate vascular functions, while excessive ROS production may exploit dysregulated dynamics injury. Herein, we survey how and, vice versa, generation the handling machinery promote dysfunction. elicit by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated entry (SOCE), multiple isoforms transient receptor potential (TRP) channels. ROS-induced permeability, angiogenesis, vasorelaxing mediators be exploited therapeutic rescue neurovascular coupling, cancer regression. However, an [Ca2+]i induced formation result dysfunction, inflammatory diseases, metabolic disorders, pulmonary artery hypertension. This information could pave way design alternative treatments interfere with life-threatening interconnection between signaling under pathological conditions.

Язык: Английский

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Signaling pathways in brain ischemia: Mechanisms and therapeutic implications

Pharmacology & Therapeutics, Год журнала: 2023, Номер 251, С. 108541 - 108541

Опубликована: Окт. 1, 2023

Язык: Английский

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