Mitochondrial and cellular reactive oxygen species (ROS) play important roles in both physiological and pathological processes. Different ROS, such as superoxide (O2(•-)), hydrogen peroxide, and ...peroxynitrite (ONOO(-)), stimulate distinct cell-signaling pathways and lead to diverse outcomes depending on their amount and subcellular localization. A variety of methods have been developed for ROS detection; however, many of these methods are not specific, do not allow subcellular localization, and can produce artifacts. In this review, we will critically analyze ROS detection and present advantages and the shortcomings of several available methods.
In the past decade, a number of new fluorescent probes, electron-spin resonance approaches, and immunoassays have been developed. These new state-of-the-art methods provide improved selectivity and subcellular resolution for ROS detection.
Although new methods for HPLC superoxide detection, application of fluorescent boronate-containing probes, use of cell-targeted hydroxylamine spin probes, and immunospin trapping have been available for several years, there has been lack of translation of these into biomedical research, limiting their widespread use.
Additional studies to translate these new technologies from the test tube to physiological applications are needed and could lead to a wider application of these approaches to study mitochondrial and cellular ROS.
The immunology of hypertension Norlander, Allison E; Madhur, Meena S; Harrison, David G
The Journal of experimental medicine,
01/2018, Letnik:
215, Številka:
1
Journal Article
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Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter ...target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases.
For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of ...experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
Inflammation in Hypertension Xiao, Liang; Harrison, David G.
Canadian journal of cardiology,
05/2020, Letnik:
36, Številka:
5
Journal Article
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For more than 50 years, evidence has accumulated that inflammation contributes to the pathogenesis of hypertension. Immune cells have been observed in vessels and kidneys of hypertensive humans. ...Biomarkers of inflammation, including high sensitivity C-reactive protein, various cytokines, and products of the complement pathway are elevated in humans with hypertension. Emerging evidence suggests that hypertension is accompanied and indeed initiated by activation of complement, the inflammasome, and by a change in the phenotype of circulating immune cells, particularly myeloid cells. High-dimensional transcriptomic analyses are providing insight into new subclasses of immune cells that are likely injurious in hypertension. These inflammatory events are interdependent and there is ultimately engagement of the adaptive immune system through mechanisms involving oxidative stress, modification of endogenous proteins, and alterations in antigen processing and presentation. These observations suggest new therapeutic opportunities to reduce end organ damage in hypertension might be used and guided by levels of inflammatory biomarkers.
Les données recueillies depuis plus de 50 ans montrent que l’inflammation participe à la pathogenèse de l’hypertension. Des cellules immunitaires ont été détectées dans les vaisseaux sanguins et les reins de sujets hypertendus. Des biomarqueurs de l’inflammation, y compris la protéine C réactive à haute sensibilité, diverses cytokines et les produits de la voie d’activation du complément, se trouvent en quantités élevées chez les patients hypertendus. De nouvelles données semblent indiquer que l’hypertension est accompagnée et même déclenchée par l’activation du complément et de l’inflammasome, ainsi que par un changement du phénotype des cellules immunitaires circulantes, en particulier les cellules myéloïdes. Des analyses transcriptomiques de grande dimension permettent de mieux connaître les nouvelles sous-classes de cellules immunitaires susceptibles d’être préjudiciables dans l’hypertension. Les événements inflammatoires observés sont interdépendants et le système immunitaire adaptatif finit par être mobilisé par des mécanismes mettant en jeu le stress oxydatif, la modification de protéines endogènes et l’altération du traitement et de la présentation des antigènes. Ces observations laissent entrevoir la possibilité de réduire les lésions aux organes cibles chez les patients hypertendus grâce à de nouvelles options thérapeutiques fondées sur les taux des biomarqueurs de l’inflammation.
Adipose tissue (AT) dysfunction, characterized by loss of its homeostatic functions, is a hallmark of non-communicable diseases. It is characterized by chronic low-grade inflammation and is observed ...in obesity, metabolic disorders such as insulin resistance and diabetes. While classically it has been identified by increased cytokine or chemokine expression, such as increased MCP-1, RANTES, IL-6, interferon (IFN) gamma or TNFα, mechanistically, immune cell infiltration is a prominent feature of the dysfunctional AT. These immune cells include M1 and M2 macrophages, effector and memory T cells, IL-10 producing FoxP3+ T regulatory cells, natural killer and NKT cells and granulocytes. Immune composition varies, depending on the stage and the type of pathology. Infiltrating immune cells not only produce cytokines but also metalloproteinases, reactive oxygen species, and chemokines that participate in tissue remodelling, cell signalling, and regulation of immunity. The presence of inflammatory cells in AT affects adjacent tissues and organs. In blood vessels, perivascular AT inflammation leads to vascular remodelling, superoxide production, endothelial dysfunction with loss of nitric oxide (NO) bioavailability, contributing to vascular disease, atherosclerosis, and plaque instability. Dysfunctional AT also releases adipokines such as leptin, resistin, and visfatin that promote metabolic dysfunction, alter systemic homeostasis, sympathetic outflow, glucose handling, and insulin sensitivity. Anti-inflammatory and protective adiponectin is reduced. AT may also serve as an important reservoir and possible site of activation in autoimmune-mediated and inflammatory diseases. Thus, reciprocal regulation between immune cell infiltration and AT dysfunction is a promising future therapeutic target.
Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but ...specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.
We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension.
To test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in
mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM vascular cell adhesion molecule-1, ICAM intercellular adhesion molecule-1, and MCP1 monocyte chemoattractant protein 1), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects.
We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.
Oxidative Stress and Hypertensive Diseases Loperena, Roxana; Harrison, David G
Medical clinics of North America/The Medical clinics of North America,
01/2017, Letnik:
101, Številka:
1
Journal Article
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It has become clear that reactive oxygen species (ROS) contribute to the development of hypertension via myriad effects. ROS are essential for normal cell function; however, they mediate pathologic ...changes in the brain, the kidney, and blood vessels that contribute to the genesis of chronic hypertension. There is also emerging evidence that ROS contribute to immune activation in hypertension. This article discusses these events and how they coordinate to contribute to hypertension and its consequent end-organ damage.
Dr Irvine Page proposed the Mosaic Theory of Hypertension in the 1940s advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. ...Over the years, Dr Page modified his paradigm, and new concepts regarding oxidative stress, inflammation, genetics, sodium homeostasis, and the microbiome have arisen that allow further refinements of the Mosaic Theory. A constant feature of this approach to understanding hypertension is that the various nodes are interdependent and that these almost certainly vary between experimental models and between individuals with hypertension. This review discusses these new concepts and provides an introduction to other reviews in this compendium of
.
Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)‐induced ...hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P < 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P < 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P< 0.05), which induced T‐cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES–/– knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES–/–), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN‐γ‐producing CD8+ and double‐negative CD3+CD4–CD8– T cells in perivascular space and reduced vascular oxidative stress while FoxP3+ T‐regulatory cells were unaltered. IFN‐γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow‐mediated dilatation (R = –0.3, P < 0.01) or endothelial injury marker von Willebrand factor (R= +0.3; P< 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.—Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T‐cell accumulation, and vascular dysfunction in hypertension. FASEB J. 30, 1987–1999 (2016). www.fasebj.org