Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium

Qian, Jin; Fulton, David

doi:10.3389/fphys.2013.00347

Cited by 142 publications

(128 citation statements)

References 182 publications

(230 reference statements)

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“…Conversely, mitochondrial depolarization in cerebral endothelial cells leads to activation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) by increasing [Ca 2ϩ ] i as well as by increasing phosphorylation of eNOS via the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) pathway (22). Endothelial NO then diffuses to adjacent vascular smooth muscle and enhances the intrinsic relaxant effects through a cGMP-dependent mechanism (33). Little is known about the relationships between mitochondrial membrane potential and NOS activation in other cell types of the neurovascular unit such as cortical neurons and perivascular nerves.…”

Section: The Current Study Provides Evidence That Pharmacological Depmentioning

confidence: 99%

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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-The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial K ATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries. MITOCHONDRIAL MEMBRANE POTENTIAL is a critical regulator of cellular activity and survival and is controlled by a variety of factors including the ATP-sensitive potassium (mitoK ATP ) channels located on the inner mitochondrial membrane (2). Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2). Signaling events following mitochondrial depolarization appear to be diverse in the various cell types comprising the neurovascular unit (cerebral vascular endothelium and smooth muscle, perivascular neurons, parenchymal neurons, and glia). Both BMS and diazoxide applications result in dilation of isolated cerebral arteries; however, individual effects on vascular smooth muscle and endothelium, which contribute to the overall vascular effect, are completely different (20,22,35,42). Thus BMS and diazoxide relax cerebral vascular smooth muscle cells via generation of localized calcium sparks by sarcoplasmic reticulum linked to mitochondrial depolarization, resulting in decreased global intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (20, 42). Conversely, mitochondrial depolarization in cerebral endothe...

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Section: The Current Study Provides Evidence That Pharmacological Depmentioning

confidence: 99%

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…AMPK and Akt are regarded as two of the most important upstream regulators of eNOS activation via Ser 1177 phosphorylation. (48) In the present study, fenofibrate pretreatment increased activated AMPK (phospho AMPK Thr 172) levels compared to TNF-alpha only treatment, which corresponds with the increased activation of eNOS. In this regard, fenofibrate has previously been associated with increased phosphorylation of AMPK (Thr 172) in a variety of endothelial cell types; (9,37,49,50) however, none of these studies were conducted in the context of TNF-alpha induced injury.…”

Section: Discussionmentioning

confidence: 73%

Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha

Westcott

Genis

Mthethwa

et al. 2017

SAHJ

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“…It is a dimeric structure in their active form containing two identical monomers of 134 kD represented by a reductase domain containing the binding sites for nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD). While an oxidase domain comprises the binding sites for the heme group, zinc, the cofactor tetrahydrobiopterin (BH4), and the substrate L-arginine [26]. The reductase domain is attached to the oxidase domain via calmodulin-binding sequence [27].…”

Section: Endothelial Nitric Oxide Synthase (Enos)mentioning

confidence: 99%

Role of Endothelial Nitric Oxide Synthase in Breast Cancer

Aiyengar¹,

Padala²,

Rani³

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Breast cancer (BC) is the most common form of carcinoma and a primary cause of morbidity and mortality globally. Oxidative stress represents as an important factor in carcinogenesis and may play a role in initiation and progression of tumors. Oxidative stress-induced NO• damage to DNA includes a multitude of lesions, many of which are mutagenic and have multiple roles in cancer and aging. It is caused by an unfavorable balance between reactive oxygen species/reactive nitrogen species (ROS/RNS) and antioxidant defenses. ROS/RNS are generated during normal cellular metabolism, as a result of the influence of various environmental factors, as well as during pathological processes.Nitric oxide (NO•) is a ubiquitous, short-lived free radical produced from L-arginine by nitric oxide synthases (NOSs), and isoforms of NOS exist, depending on the site of origin: endothelial (eNOS), neuronal (nNOS), mitochondrial (mtNOS), and inducible (iNOS). eNOS is responsible for the endothelial synthesis of NO• and has shown to modulate cancer-related events such as inflammation, angiogenesis, apoptosis, cell cycle, invasion, and metastasis. Genetic studies also showed that eNOS gene polymorphisms are associated with the development of breast cancer. Therefore, selective targeting of eNOS may prove a potential strategy for prevention and treatment of breast cancer.

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Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium

Cited by 142 publications

References 182 publications

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha

Role of Endothelial Nitric Oxide Synthase in Breast Cancer

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