Reactive Nitrogen Species: Molecular Mechanisms and Potential Significance in Health and Disease

Reactive nitrogen species (RNS) are various nitric oxide–derived compounds, including nitroxyl anion, nitrosonium cation, higher oxides of nitrogen, S-nitrosothiols, and dinitrosyl iron complexes. RNS have been recognized as playing a crucial role in the physiologic regulation of many, if not all, living cells, such as smooth muscle cells, cardiomyocytes, platelets, and nervous and juxtaglomerular cells. They possess pleiotropic properties on cellular targets after both posttranslational modifications and interactions with reactive oxygen species. Elevated levels of RNS have been implicated in cell injury and death by inducing nitrosative stress. The aim of this comprehensive review is to address the mechanisms of formation and removal of RNS, highlighting their potential cellular targets: lipids, DNA, and proteins. The specific importance of RNS and their paradoxic effects, depending on their local concentration under physiologic conditions, is underscored. An increasing number of compounds that modulate RNS processing or targets are being identified. Such compounds are now undergoing preclinical and clinical evaluations in the treatment of pathologies associated with RNS-induced cellular damage. Future research should help to elucidate the involvement of RNS in the therapeutic effect of drugs used to treat neurodegenerative, cardiovascular, metabolic, and inflammatory diseases and cancer

Microparticles harboring sonic hedgehog: Role in angiogenesis regulation

Sonic Hedgehog (Shh) is a morphogen involved in embryonic development of nervous system. Also, it has been shown that recombinant Shh can modulate angiogenesis under ischemic conditions. However, angiogenic effects of endogenous Shh have not been completely elucidated. Using small membrane-derived vesicles expressing Shh (MPsShh+), we have shown that, although MPsShh+ decrease endothelial cell proliferation and migration, they are able to favour angiogenesis through the increase of both endothelial cell adhesion and expression of pro-angiogenenic factors. Activation of proteins implicated in cell adhesion, such as Rho A, as well as upregulation of pro-angiogenic factors were sensitive to inhibition of Shh pathway. Although whole composition of MPsShh+ needs to be characterized to understand potential effects of MPsShh+, these results highlight a new role of MPsShh+ in vascular pathophysiology and may have significant implication for therapy in pathologies associated with altered angiogenesis in order to re-address angiogenic switch

Engineered microparticles bearing the morphogen Sonic Hedgehog protect endothelial cells against actinomycin D-induced apoptosis

It has been reported that microparticles generated from T lymphocytes undergoing activation and apoptosis, bear the morphogen Sonic Hedgehog (MPsShh+), and possessed the dual ability to increase NO and reduce ROS productions. Here, we investigated whether MPsShh+ protected human umbical vein endothelial cells (HUVECs) against actinomycin D (ActD)-induced apoptosis. MPsShh+ were obtained by activation of human lymphocyte with phytohemagglutinin and then, by stimulation with phorbol-12 myristate-13 acetate and ActD. HUVECs were grown for 24 h in absence or presence of pro-apoptotic agent, ActD (1 μg/mL), and/or 10 μg protein/mL of MPsShh+. Apoptosis evaluation was based on flow cytometry, TUNEL labelling and cytochrome c release. We showed that MPsShh+ treatment significantly prevented HUVECs apoptosis evoked by ActD. Also, caspases inhibitor z-vad.fmk (50 μM ) reduced cell death either in presence or in absence of MPsShh+, indicating the implication of caspases in ActD-induced apoptosis. To investigate the implication of Shh pathway in this effect, its agonist SAG and its antagonist CUR61414 were tested. SAG reduced apoptosis in a dose-dependent manner; by itself, CUR61414 had no effect on its own but abolished the antiapoptotic effect of MPsShh, revealing a contribution of Shh pathway. In contrast, MPsShh+ were still able to reduce apoptosis in the presence of NO synthase inhibitor, L-NA (100 μM ), or when the PI3-kinase and ERK were inhibited with LY294002 (10 μM ) and U0126 (10 μM ) respectively, showing that these pathways were not associated with protection against apoptosis. Besides, we explored changes in ROS production at different times, by electronic paramagnetic resonance. ROS levels were increased in ActD-treated cells at 2 h and 10 h. This elevation was prevented by MPsShh+ only at 2 h. When sources of ROS, xanthine oxidase, NAD(P)H oxidase and respiratory chain complex I, were inhibited using allopurinol (50 μM ), apocynin (100 μM ) and rotenone (5 μM), respectively, we found that only rotenone reduced ActD-induced apoptosis. Also, the superoxide dismutase (SOD) mimetic, MnTMPyP (100 μM ), reduced ActD-evoked cell death and the protective effect of MPsShh+. These results indicate that, under these experimental conditions, MPsShh+ may act in the early phase of apoptosis at mitochondrial level and behave as a SOD mimetic. These findings provide additional mechanisms by which MPsShh+ exert their vasculoprotective effects, preserving integrity of endothelial monolayer. Supported by ANR-07-PHYSIO-010-01

Extracellular vesicles: New players in cardiovascular diseases

Extracellular vesicles, particles released by all cell types, represent a new way to convey information between cells such as proteins, second messengers, and genetic information to modify the phenotype and function of the target cells. Recent data suggest that extracellular vesicles play a crucial role in both physiology and pathology, including coagulation, angiogenesis, cell survival, modulation of the immune response, and inflammation. Thus extracellular vesicles participate in the processes of cardiovascular diseases from atherosclerosis, myocardial infarction to heart failure. Consequently, extracellular vesicles can potentially be exploited for therapy, prognosis, and biomarkers for health and disease. This review focuses on the role of extracellular vesicles in the development of cardiovascular diseases, as well as the deleterious and beneficial effects that they may provide in vascular cells and myocardium

The role of Smoothened and Hh signaling in neovascularization

New vessel formation plays a key role not only in physiological processes such as embryonic development and wound repair but also during several pathological situations. In this respect, favoring neovascularization represents a promising therapeutic approach that would allow inducing tissue repair. Among the candidate proteins able to modulate neovascularization, evidence show that the administration of recombinant hedgehog (Hh) protein, gene, or cell therapy based on Hh transfer or using extracellular vesicles as vectors enhance new vessel formation. Here, we summarized the role of Hh pathway on angiogenesis and its therapeutic potential during myocardial infarction and diabetes

Analyses of long-term measurements (2005-2012) of 7Be concentrations in surface air aerosols

Studies of radionuclide activities in aerosol particles provide a mean for evaluating the integrated effects of transport and meteorology on the atmospheric loadings of substances with different sources. The aim of the present study is to explain the behaviour of aerosols associated with 7Be (T1/2=53.3 days) in the surface atmosphere using exploratory data analysis to obtain information on their possible mechanisms of transport and deposition. This naturally occurring radionuclide is an important isotope in studying atmospheric processes because of its convenient half-life and sufficiently detectable -radiation (E = 0.477 MeV), which has served for studying precipitation scavenging, vertical and horizontal removal of air masses, aerosol transit and residence times in the troposphere [1]

Variations of PM10 and its relationship with 7Be and 210Pb measurements at Malaga (Southeastern coast of Spain)

INTRODUCTION Levels of particulate matter fraction PM10 were monitored between 2009 and 2011 in Malaga (Spain) in one of the Atmospheric Pollution Monitoring network managed by the Environmental Health Service of the Andalusian Government. Long-term measurements of cosmogenic radionuclides such as 7Be provide important data in studying global atmospheric processes and comparing environmental impact of radioactivity from man-made sources to natural ones. 7Be is a natural radionuclide tracer of aerosols originated over a range of high altitudes in the atmosphere. On the other hand, 210Pb is produced by radioactive decay from its progenitor, 222Rn, which emanates primarily from land surface. Therefore, 210Pb in the air is an effective tracer of the continental surface air mass. The variation of the data with time was studied by time series analyses and seasonal patterns were identified. The study of air back-trajectories were computed by means of the Hybrid Single-Particle Lagrangian Integrated Trajectories (HYSPLIT) trajectory model (Draxler, 1994) using meteorological data supplied by the US National Climatic Data Centr

Atmospheric fluxes of radionuclides on monthly time-scale in Málaga (Spain)

ABSTRACT.- Bulk atmospheric deposition of gamma radionuclides ( 7Be, 210Pb and 40K ) has been measured at Málaga (4º 28´80′′ W; 36º 43′ 40′N) at a coastal Mediterranean station in the south of Spain, from January 2005 through December 2012 for monthly period

Long-term atmospheric fluxes of radionuclides at a coastal Mediterranean station

7Be is one of the radionuclide produced by spallation reactions of cosmic rays with light atmospheric nuclei. 7Be rapidly associates primarily with submicron-sized aerosol particles. Gravitational settling and precipitation processes largely accomplish transfer to the earth’s surface. 210Pb which is one of the natural radionuclide of the 238U series is widely used as a tracer. 210Pb depositional pattern gave us information on continental aerosols in lower troposphere. These two radionuclides with their different sources and therefore are useful to understand the mechanisms of aerosol removal from the atmosphere. These radionuclides have measured routinely in many places in order to study the description of environmental processes such as aerosol transit and residence times in the troposphere , aerosol deposition velocities and aerosol trapping by ground vegetation.40K has been associated with the arrival of coarse re-suspended material from the Africa continent. The bulk atmospheric deposition of 7Be , 210Pb and 40K has been measured at Málaga , south-eastern Spain, from January 2005 to December 2012 for monthly periods.CS