Redox Signaling, Vascular Function, and Hypertension

Lee, Moo Yeol; Griendling, Kathy K.

doi:10.1089/ars.2007.1986

Cited by 216 publications

(193 citation statements)

References 245 publications

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“…These include proinflammatory responses, oxidative modification of proteins that regulate vascular contraction and relaxation, fibrosis and calcification, altered calcium homeostasis and redox-sensitive pro-inflammatory and pro-fibrotic transcription factor activation. Xanthine oxidase is another potential source of ROS within the vasculature that may contribute to oxidative stress associated with hypertension, although its precise role remains to be fully understood 62 . The mitochondrial electron transport chain can also produce superoxide as a by-product of electron transport during oxidative phosphorylation and may also therefore contribute to oxidative stress associated with hypertension 62 .…”

Section: Oxidative Stressmentioning

confidence: 99%

“…Xanthine oxidase is another potential source of ROS within the vasculature that may contribute to oxidative stress associated with hypertension, although its precise role remains to be fully understood 62 . The mitochondrial electron transport chain can also produce superoxide as a by-product of electron transport during oxidative phosphorylation and may also therefore contribute to oxidative stress associated with hypertension 62 .…”

Section: Oxidative Stressmentioning

confidence: 99%

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Drug Treatment of Hypertension: Focus on Vascular Health

Cameron

Lang

Touyz

2016

Drugs

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Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure elevation, the vascular system is particularly important, because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high blood pressure have greater efficacy for reducing cardiovascular risk than drugs that reduce blood pressure but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme Key Points• Hypertension is characterized by a vascular phenotype of endothelial dysfunction and structural remodeling.• Anti-hypertensive drugs that target the vascular changes associated with hypertension appear to be most efficacious• New anti-hypertensive drugs should promote vascular health as well as reducing blood pressure 3

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Section: Oxidative Stressmentioning

confidence: 99%

Section: Oxidative Stressmentioning

confidence: 99%

Drug Treatment of Hypertension: Focus on Vascular Health

Cameron

Lang

Touyz

2016

Drugs

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“…66 Circulating Biochemical Markers of Vascular Inflammation Angiotensin II has been identified in studies of tissues and experimental animals as a proinflammatory molecule that stimulates the formation of reactive oxygen species, resulting in the upregulation of inflammatory mediators such as the transcription factor NF-jB and increased formation of chemokines, C-reactive protein (CRP), and adhesion molecules and activation of T lymphocytes that contribute to both BP elevation and atherosclerosis. 2,3,67 An increase in circulating markers of inflammation have been documented in patients with hypertension, obesity, and diabetes, and one of these agents, CRP, has been reported to independently predict CV risk. 68 In this context, ARBs along with other RAS blockers should be ideal drugs to block these proinflammatory actions of angiotensin II with a consequent reduction in the levels of circulating markers of inflammation.…”

Section: Prevention Of Hypertensionmentioning

confidence: 99%

Angiotensin Receptor Blockers: Pharmacology, Efficacy, and Safety

Taylor

Siragy

Nesbitt

2011

The Journal of Clinical Hypertension

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Key Points and Practical Recommendations• The angiotensin receptor blockers are highly effective antihypertensive agents that are also particularly well tolerated.• There are no major differences in efficacy or other clinical characteristics among older drugs in this class, although some of the newer agents may more effectively reduce blood pressure than older agents.• Major randomized clinical trials have demonstrated that angiotensin receptor blockers provide significant outcomes benefits in conditions such as diabetic nephropathy, chronic heart failure or heart failure following myocardial infarction, hypertension with left ventricular hypertrophy and in patients whose histories of previous events or complicated diabetes puts them at high cardiovascular risk.• In treating hypertension, angiotensin receptor blockers can be used as first-line therapy or added at later stages of treatment titration.• These drugs are very effective in combination with thiazide diuretics or calcium channel blockers and there are several single-pill, fixed-dose combinations of angiotensin receptor blockers with hydrochlorothiazide, amlodipine, or aliskiren. These combinations can be given as initial therapy (where appropriate) or later in the course of treatment. Three-drug combinations (angiotensin receptor blocker plus amlodipine plus hydrochlorothiazide and angiotensin receptor blocker plus aliskiren plus hydrochlorothiazide) are also available. J Clin Hypertens (Greenwich). 2011;13:677-686. Ó2011 Wiley Periodicals, Inc.The renin-angiotensin-aldosterone system (RAAS) plays an important role in protecting vertebrates against cardiovascular collapse due to hypotension and volume loss in the event of traumatic injury that involves blood loss. In certain humans, however, inappropriate or exaggerated activity of the RAAS contributes to the development of hypertension and the initiation of a molecular cascade in tissues with consequent injury to critical organs such as the brain, kidneys, heart, and blood vessels. 1-3 As understanding of the pathologic role of the RAAS in hypertensive vascular disease has unfolded during the past century, so has the interest in developing drugs that could interdict specific components of the RAAS. The first of the RAAS-blocking drugs to become commercially available were the aldosterone antagonists in the 1970s, followed by the angiotensin-converting enzyme (ACE) inhibitors in the 1980s and the angiotensin II receptor blockers (ARBs) in the 1990s. Unlike ACE inhibitors that inhibit the conversion of angiotensin I to II, ARBs bind to the angiotensin II AT 1 receptor, thereby inhibiting the cellular actions of angiotension II mediated by the receptor in which the tissue is located. During the past 20 years, studies in the laboratory and clinic have documented that ARBs, either alone or in combination with drugs of other classes, reduce blood pressure (BP) in hypertensive animals and humans; reduce rates of myocardial infarction (MI), stroke, and progression of renal impairment; and positively impact oth...

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“…superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1)(2)(3)(4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.…”

mentioning

confidence: 99%

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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Oxidative stress arises from an imbalance in the production and scavenging rates of reactive oxygen species (ROS) and is a key factor in the pathophysiology of cardiovascular disease and aging. The presence of parallel pathways and multiple intracellular compartments, each having its own ROS sources and antioxidant enzymes, complicates the determination of the most important regulatory nodes of the redox network. Here we quantified ROS dynamics within specific intracellular compartments in the cytosol and mitochondria and determined which scavenging enzymes exert the most control over antioxidant fluxes in H9c2 cardiac myoblasts. We used novel targeted viral gene transfer vectors expressing redox-sensitive GFP fused to sensor domains to measure H 2 O 2 or oxidized glutathione. Using genetic manipulation in heart-derived H9c2 cells, we explored the contribution of specific antioxidant enzymes to ROS scavenging and glutathione redox potential within each intracellular compartment. Our findings reveal that antioxidant flux is strongly dependent on mitochondrial substrate catabolism, with availability of NADPH as a major rate-controlling step. Moreover, ROS scavenging by mitochondria significantly contributes to cytoplasmic ROS handling. The findings provide fundamental information about the control of ROS scavenging by the redox network and suggest novel interventions for circumventing oxidative stress in cardiac cells. Reactive oxygen species (ROS)2 serve as both signaling molecules and destructive agents, requiring cells to finely regulate their levels. Antioxidant enzymes catalyze ROS conversion directly via an active-site metal ion (e.g. superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1-4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8, 9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias. The dynamics and steady-state levels of ROS in local intracellular domains are determined by the rates of free radical generation and scavenging. Failure to scavenge free radicals via antioxidant fluxes can trigger a vicious cycle of dysfunction, leading to death (10). Recent studies have demonstrated that antioxidant enzymes targeted to the mitochondria, but not the cytoplasm, protect agai...

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Redox Signaling, Vascular Function, and Hypertension

Cited by 216 publications

References 245 publications

Drug Treatment of Hypertension: Focus on Vascular Health

Drug Treatment of Hypertension: Focus on Vascular Health

Angiotensin Receptor Blockers: Pharmacology, Efficacy, and Safety

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

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