Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease.
01 Oct 2013-Antioxidants & Redox Signaling (Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA)-Vol. 19, Iss: 10, pp 1085-1094
TL;DR: Interestingly, the overexpression of mitochondrial thioredoxin 2 or mitochondrial superoxide dismutase attenuates Ang II-induced hypertension, which demonstrates the importance of mitochondrial ROS in AngII-mediated cardiovascular diseases.
Abstract: Significance: The role of reactive oxygen species (ROS) in angiotensin II (AngII) induced endothelial dysfunction, cardiovascular and renal remodeling, inflammation, and fibrosis has been well documented. The molecular mechanisms of AngII pathophysiological activity involve the stimulation of NADPH oxidases, which produce superoxide and hydrogen peroxide. AngII also increases the production of mitochondrial ROS, while the inhibition of AngII improves mitochondrial function; however, the specific molecular mechanisms of the stimulation of mitochondrial ROS is not clear. Recent Advances: Interestingly, the overexpression of mitochondrial thioredoxin 2 or mitochondrial superoxide dismutase attenuates AngII-induced hypertension, which demonstrates the importance of mitochondrial ROS in AngII-mediated cardiovascular diseases. Critical Issues: Although mitochondrial ROS plays an important role in normal physiological cell signaling, AngII, high glucose, high fat, or hypoxia may cause the overproduction...
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TL;DR: How the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype is investigated.
Abstract: Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.
646 citations
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...Hyperglycemia along with elevated free fatty acid levels induce ROS production and the secretion of pro-inflammatory cytokines that additively provoke mitochondrial and DNA damage [119]....
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TL;DR: It is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
Abstract: The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG I...
618 citations
Journal Article•
TL;DR: Mitochondrial dysfunction in response to Ang II modulates endothelial NO˙ and &OV0151; generation, which in turn has ramifications for development of endothelial dysfunction.
Abstract: Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO˙) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO˙ was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography –based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H2O2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), NG-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22phox subunit of NADPH oxidase with small interfering RNA also inhibited Ang II–mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II–induced decrease in endothelial NO˙ and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C–dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO˙ and &OV0151; generation, which in turn has ramifications for development of endothelial dysfunction.
579 citations
Royal Melbourne Hospital1, Yale University2, European University3, Cedars-Sinai Medical Center4, University of Parma5, Icahn School of Medicine at Mount Sinai6, University of Duisburg-Essen7, Federal University of São Paulo8, Pennsylvania State University9, University of Paris10, Boston University11, Leipzig University12, Imperial College London13, University of Michigan14, Korea University Medical Center15, University of Birmingham16, University of California, San Francisco17, Vanderbilt University18, University of Tsukuba19, Royal Adelaide Hospital20, Cleveland Clinic21, McGill University22
TL;DR: The working group proposes the following working definition of atrial cardiomyopathy: ‘Any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations’ (Table 1).
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TL;DR: How adipose tissue becomes inflamed in obesity is described, ways these mechanisms impact cancer development are summarized, and their role in four adipose-associated cancers that demonstrate elevated incidence or mortality in obesity are discussed.
Abstract: Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects. Dysregulated metabolism t...
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References
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Boston University1, Rush University Medical Center2, University of Tennessee Health Science Center3, University of Michigan4, University at Buffalo5, University of Mississippi6, University of Miami7, University of Alabama at Birmingham8, Case Western Reserve University9, National Institutes of Health10
TL;DR: The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated, and empathy builds trust and is a potent motivator.
Abstract: "The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure" provides a new guideline
for hypertension prevention and management. The following are the key messages(1) In persons older than 50 years, systolic blood pressure (BP) of
more than 140 mm Hg is a much more important cardiovascular disease
(CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75
mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive
at 55 years of age have a 90% lifetime risk for developing hypertension; (3)
Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80
to 89 mm Hg should be considered as prehypertensive and require health-promoting
lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should
be used in drug treatment for most patients with uncomplicated hypertension,
either alone or combined with drugs from other classes. Certain high-risk
conditions are compelling indications for the initial use of other antihypertensive
drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor
blockers, β-blockers, calcium channel blockers); (5) Most patients with
hypertension will require 2 or more antihypertensive medications to achieve
goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes
or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal
BP, consideration should be given to initiating therapy with 2 agents, 1 of
which usually should be a thiazide-type diuretic; and (7) The most effective
therapy prescribed by the most careful clinician will control hypertension
only if patients are motivated. Motivation improves when patients have positive
experiences with and trust in the clinician. Empathy builds trust and is a
potent motivator. Finally, in presenting these guidelines, the committee recognizes
that the responsible physician's judgment remains paramount.
24,988 citations
TL;DR: What was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s are described, including a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle.
Abstract: It’s a great honor to join the exceptional club of Banting Award winners, many of whom were my role models and mentors. In addition, giving the Banting Lecture also has a very personal meaning to me, because without Frederick Banting, I would have died from type 1 diabetes when I was 8 years old. However, it was already apparent at the time I was diagnosed that for too many people like me, Banting’s discovery of insulin only allowed them to live just long enough to develop blindness, renal failure, and coronary disease. For example, when I started college, the American Diabetes Association’s Diabetes Textbook had this to say to my parents: “The person with type 1 diabetes can be reassured that it is highly likely that he will live at least into his 30s.” Not surprisingly, my parents did not find this particularly reassuring.
At the same time we were reading this in 1967, however, the first basic research discovery about the pathobiology of diabetic complications had just been published in Science the previous year. In my Banting Lecture today, I am thus going to tell you a scientific story that is also profoundly personal.
I’ve divided my talk into three parts. The first part is called “pieces of the puzzle,” and in it I describe what was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s. In the second part, I present a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle. Finally, in the third part, I focus on three examples of novel therapeutic approaches for the prevention and treatment of diabetic complications, which are all based on the new paradigm of a unifying mechanism for the pathogenesis of diabetic complications. …
4,691 citations
TL;DR: Vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix and have been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.
Abstract: Reactive oxygen species have emerged as important molecules in cardiovascular function. Recent work has shown that NAD(P)H oxidases are major sources of superoxide in vascular cells and myocytes. The biochemical characterization, activation paradigms, structure, and function of this enzyme are now partly understood. Vascular NAD(P)H oxidases share some, but not all, characteristics of the neutrophil enzyme. In response to growth factors and cytokines, they produce superoxide, which is metabolized to hydrogen peroxide, and both of these reactive oxygen species serve as second messengers to activate multiple intracellular signaling pathways. The vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix. They have also been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.
2,959 citations
TL;DR: Professional phagocytes generate high levels of reactive oxygen species (ROS) using a superoxide-generating NADPH oxidase as part of their armoury of microbicidal mechanisms, leading to the concept that ROS are 'intentionally' generated in these cells with distinctive cellular functions related to innate immunity, signal transduction and modification of the extracellular matrix.
Abstract: Professional phagocytes generate high levels of reactive oxygen species (ROS) using a superoxide-generating NADPH oxidase as part of their armoury of microbicidal mechanisms. The multicomponent phagocyte oxidase (Phox), which has been well characterized over the past three decades, includes the catalytic subunit gp91phox. Lower levels of ROS are seen in non-phagocytic cells, but are usually thought to be 'accidental' byproducts of aerobic metabolism. The discovery of a family of superoxide-generating homologues of gp91phox has led to the concept that ROS are 'intentionally' generated in these cells with distinctive cellular functions related to innate immunity, signal transduction and modification of the extracellular matrix.
2,865 citations
TL;DR: Results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagic in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
Abstract: Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
1,390 citations