A novel long non-coding natural antisense RNA is a negative regulator of Nos1 gene expression

Long non-coding natural antisense transcripts (NATs) are widespread in eukaryotic species. Although recent studies indicate that long NATs are engaged in the regulation of gene expression, the precise functional roles of the vast majority of them are unknown. Here we report that a long NAT (Mm-antiNos1 RNA) complementary to mRNA encoding the neuronal isoform of nitric oxide synthase (Nos1) is expressed in the mouse brain and is transcribed from the non-template strand of the Nos1 locus. Nos1 produces nitric oxide (NO), a major signaling molecule in the CNS implicated in many important functions including neuronal differentiation and memory formation. We show that the newly discovered NAT negatively regulates Nos1 gene expression. Moreover, our quantitative studies of the temporal expression profiles of Mm-antiNos1 RNA in the mouse brain during embryonic development and postnatal life indicate that it may be involved in the regulation of NO-dependent neurogenesis

Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide.

In the vascular system, nitric oxide is generated by endothelial NO synthase (eNOS). NO has pleiotropic effects, most of which are believed to be atheroprotective. Therefore, it has been argued that patients suffering from cardiovascular disease could benefit from an increase in eNOS activity. However, increased NO production can cause oxidative damage, cell toxicity, and apoptosis and hence could be atherogenic rather than beneficial. To study the in vivo effects of increased eNOS activity, we created transgenic mice overexpressing human eNOS. Aortic blood pressure was approximately 20 mm Hg lower in the transgenic mice compared with control mice because of lower systemic vascular resistance. The effects of eNOS overexpression on diet-induced atherosclerosis were studied in apolipoprotein E-deficient mice. Elevation of eNOS activity decreased blood pressure ( approximately 20 mm Hg) and plasma levels of cholesterol (approximately 17%), resulting in a reduction in atherosclerotic lesions by 40%. We conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis

The endocannabinoid system:no longer anonymous in the control of nitrergic signalling?

The endocannabinoid system (ECS) is a key cellular signalling system which has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS mediated regulation of nitric oxide production, the involvement of reactive nitrogen species in regulating ECS induced signal transduction, as well as highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS - nitric oxide signalling axis in disease development, and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular and metabolic disorders

Endothelial Dysfunction in Human Essential Hypertension

Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. It is increasingly recognized that this is related to hypertension, although whether it predates essential hypertension or is a consequence of it is still unknown. In this review, we explore the mechanisms of endothelial dysfunction in essential hypertension, its prognostic significance and methods of pharmacological reversal

Neuronal nitric oxide synthase contributes to the regulation of hematopoiesis

Nitric oxide (NO) signaling is important for the regulation of hematopoiesis. However, the role of individual NO synthase (NOS) isoforms is unclear. Our results indicate that the neuronal NOS isoform (nNOS) regulates hematopolesis in vitro and in vivo. nNOS is expressed in adult bone marrow and fetal liver and is enriched in stromal cells. There is a strong correlation between expression of nNOS in a panel of stromal cell lines established from bone marrow and fetal liver and the ability of these cell lines to support hematopoietic stem cells; furthermore, NO donor can further increase this ability. The number of colonies generated in vitro from the bone marrow and spleen of nNOS-null mutants is increased relative to wild-type or inducible- or endothelial NOS knockout mice. These results describe a new role for nNOS beyond its action in the brain and muscle and suggest a model where nNOS, expressed in stromal cells, produces NO which acts as a paracrine regulator of hematopoietic stem cells

Comprehensive lung injury pathology induced by mTOR inhibitors

Molecular Targets in Oncology[Abstract] Interstitial lung disease is a rare side effect of temsirolimus treatment in renal cancer patients. Pulmonary fibrosis is characterised by the accumulation of extracellular matrix collagen, fibroblast proliferation and migration, and loss of alveolar gas exchange units. Previous studies of pulmonary fibrosis have mainly focused on the fibro-proliferative process in the lungs. However, the molecular mechanism by which sirolimus promotes lung fibrosis remains elusive. Here, we propose an overall cascade hypothesis of interstitial lung diseases that represents a common, partly underlying synergism among them as well as the lung pathogenesis side effects of mammalian target of rapamycin inhibitors

Activation of protease calpain by oxidized and glycated LDL increases the degradation of endothelial nitric oxide synthase

Oxidation and glycation of low-density lipoprotein (LDL) promote vascular injury in diabetes; however, the mechanisms underlying this effect remain poorly defined. The present study was conducted to determine the effects of ‘heavily oxidized’ glycated LDL (HOG-LDL) on endothelial nitric oxide synthase (eNOS) function. Exposure of bovine aortic endothelial cells with HOG-LDL reduced eNOS protein levels in a concentration- and time-dependent manner, without altering eNOS mRNA levels. Reduced eNOS protein levels were accompanied by an increase in intracellular Ca2+, augmented production of reactive oxygen species (ROS) and induction of Ca2+-dependent calpain activity. Neither eNOS reduction nor any of these other effects were observed in cells exposed to native LDL. Reduction of intracellular Ca2+ levels abolished eNOS reduction by HOG-LDL, as did pharmacological or genetic through calcium channel blockers or calcium chelator BAPTA or inhibition of NAD(P)H oxidase (with apocynin) or inhibition of calpain (calpain 1-specific siRNA). Consistent with these results, HOG-LDL impaired acetylcholine-induced endothelium-dependent vasorelaxation of isolated mouse aortas, and pharmacological inhibition of calpain prevented this effect. HOG-LDL may impair endothelial function by inducing calpain-mediated eNOS degradation in a ROS- and Ca2+-dependent manner

Synchrotron X-ray quantitative evaluation of transient deformation and damage phenomena in a single nickel-rich cathode particle

The performance and durability of Ni-rich cathode materials are controlled in no small part by their mechanical durability, as chemomechanical breakdown at the nano-scale leads to increased internal resistance and decreased storage capacity. The mechanical degradation is caused by the transient lithium diffusion processes during charge and discharge of layered oxide spherical cathode micro-particles, leading to highly anisotropic incompatible strain fields. Experimental characterisation of the transient mechanisms underlying crack and void formation requires the combination of very high resolution in space (sub-micron) and time (sub-second) domains without charge interruption. The present study is focused on sub-micron focused operando synchrotron X-ray diffraction and in situ Ptycho-Tomographic nano-scale imaging of a single nano-structured LiNi0.8Co0.1Mn0.1O2 core-shell particle during charge to obtain a thorough understanding of the anisotropic deformation and damage phenomena at a particle level. Preferential grain orientation within the shell of a spherical secondary cathode particle provides improved lithium transport but is also associated with spatially varying anisotropic expansion of the hexagonal unit cell in the c-axis and contraction in the a-axis. These effects were resolved in relation to the grain orientation, and the link established with the nucleation and growth of intergranular cracks and voids that causes electrical isolation of active cathode material. Coupled multi-physics Finite Element Modelling of diffusion and deformation inside a single cathode particle during charge and discharge was validated by comparison with experimental evidence and allowed unequivocal identification of key mechanical drivers underlying Li-ion battery degradation

Extrinsic neural control of nitric oxide synthase expression in the myenteric plexus of rat jejunum

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65138/1/j.1469-7793.1998.549bt.x.pd