Non-fibrillar collagens: Key mediators of post-infarction cardiac remodeling?

Cardiac remodeling is accelerated during pathological conditions and several anabolic and catabolic regulators work in concert to repair the myocardium and maintain its functionality. The fibroblasts play a major role in this process via collagen deposition as well as supplying the degradative matrix metalloproteinases. During the more acute responses to a myocardial infarction (MI) the heart relies on a more aggressive wound healing sequence that includes the myofibroblasts, specialized secretory cells necessary for infarct scar formation and thus, rescue of the myocardium. The activated fibroblasts and myofibroblasts deposit large amounts of fibrillar collagen during the post-MI wound healing phase, type I and III collagen are the most abundant collagens in the heart and they maintain the structural integrity under normal and disease states. While collagen I and III have been the traditional focus of the myocardial matrix, recent studies have suggested that the non-fibrillar collagens (types IV and VI) are also deposited during pathological wound healing and may play key roles in myofibroblast differentiation and organization of the fibrillar collagen network. This review highlights the potential roles of the non-fibrillar collagens and how they work in concert with the fibrillar collagens in mediating myocardial remodeling.     

Role of metabolically generated reactive oxygen species for lipotoxicity in pancreatic β-cells

Chronically elevated concentrations of non-esterified fatty acids (NEFAs) in type 2 diabetes may be involved in β-cell dysfunction and apoptosis. It has been shown that long-chain saturated NEFAs exhibit a strong cytotoxic effect upon insulin-producing cells, while short-chain as well as unsaturated NEFAs are well tolerated. Moreover, long-chain unsaturated NEFAs counteract the toxicity of palmitic acid. Reactive oxygen species (ROS) formation and gene expression analyses together with viability assays in different β-cell lines showed that the G-protein-coupled receptors 40 and 120 do not mediate lipotoxicity. This is independent from the role, which these receptors, specifically GPR40, play in the potentiation of glucose-induced insulin secretion by saturated and unsaturated long-chain NEFAs. Long-chain NEFAs are not only metabolized in the mitochondria but also in peroxisomes. In contrast to mitochondrial β-oxidation, the acyl-coenzyme A (CoA) oxidases in the peroxisomes form hydrogen peroxide and not reducing equivalents. As β-cells almost completely lack catalase, they are exceptionally vulnerable to hydrogen peroxide generated in peroxisomes. ROS generation in the respiratory chain is less important because overexpression of catalase and superoxide dismutase in the mitochondria do not provide protection. Thus, peroxisomally generated hydrogen peroxide is the likely ROS that causes pancreatic β-cell dysfunction and ultimately β-cell death.     

One molecule,many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species?

Melatonin is a highly conserved molecule. Its presence can be traced back to ancient photosynthetic prokaryotes. A primitive and primary function of melatonin is that it acts as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. The receptor-dependent functions of melatonin were subsequently acquired during evolution. In the current review, we focus on melatonin metabolism which includes the synthetic rate-limiting enzymes, synthetic sites, potential regulatory mechanisms, bioavailability in humans, mechanisms of breakdown and functions of its metabolites. Recent evidence indicates that the original melatonin metabolite may be N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) rather than its commonly measured urinary excretory product 6-hydroxymelatonin sulfate. Numerous pathways for AFMK formation have been identified both in vitro and in vivo. These include enzymatic and pseudo-enzymatic pathways, interactions with reactive oxygen species (ROS)/reactive nitrogen species (RNS) and with ultraviolet irradiation. AFMK is present in mammals including humans, and is the only detectable melatonin metabolite in unicellular organisms and metazoans. 6-hydroxymelatonin sulfate has not been observed in these low evolutionary-ranked organisms. This implies that AFMK evolved earlier in evolution than 6-hydroxymelatonin sulfate as a melatonin metabolite. Via the AFMK pathway, a single melatonin molecule is reported to scavenge up to 10 ROS/RNS. That the free radical scavenging capacity of melatonin extends to its secondary, tertiary and quaternary metabolites is now documented. It appears that melatonin's interaction with ROS/RNS is a prolonged process that involves many of its derivatives. The process by which melatonin and its metabolites successively scavenge ROS/RNS is referred as the free radical scavenging cascade. This cascade reaction is a novel property of melatonin and explains how it differs from other conventional antioxidants. This cascade reaction makes melatonin highly effective, even at low concentrations, in protecting organisms from oxidative stress. In accordance with its protective function, substantial amounts of melatonin are found in tissues and organs which are frequently exposed to the hostile environmental insults such as the gut and skin or organs which have high oxygen consumption such as the brain. In addition, melatonin production may be upregulated by low intensity stressors such as dietary restriction in rats and exercise in humans. Intensive oxidative stress results in a rapid drop of circulating melatonin levels. This melatonin decline is not related to its reduced synthesis but to its rapid consumption, i.e. circulating melatonin is rapidly metabolized by interaction with ROS/RNS induced by stress. Rapid melatonin consumption during elevated stress may serve as a protective mechanism of organisms in which melatonin is used as a first-line defensive molecule against oxidative damage. The oxidative status of organisms modifies melatonin metabolism. It has been reported that the higher the oxidative state, the more AFMK is produced. The ratio of AFMK and another melatonin metabolite, cyclic 3-hydroxymelatonin, may serve as an indicator of the level of oxidative stress in organisms.     

Phenylacetic acid stimulates reactive oxygen species generation and tumor necrosis factor-α secretion in vascular endothelial cells

Tumor necrosis factor (TNF)-α and oxidative stress are considered to play crucial roles in atherosclerosis and vascular calcification. "Uremic toxins" detected in patients with chronic kidney disease (CKD) could cause impaired signal transduction and dysfunction in many organs. Since phenylacetic acid (PAA), identified as one of the uremic toxins, has an inhibiting property of monocytes as well as osteoblastic cells, we examined the effects of PAA on TNF-α secretion and oxidative stress in vascular endothelial cells. In human aortic endothelial cells, TNF-α secretion was assessed after treatment with PAA using an ELISA kit and following the manufacturer's instructions. For determination of reactive oxygen species (ROS), 8-hydroxydeoxyguanosine (8-OHdG) in the culture medium was measured in the presence or absence of PAA. Treatment with PAA in aortic endothelial cells for 24 h significantly stimulated TNF-α secretion in a dose-dependent manner ranging between 0.5 and 5 mM. On the other hand, the 8-OHdG level in the culture medium was significantly increased in the cells incubated with 1 mM PAA for 12 h. To determine if PAA-induced TNF-α secretion is mediated by ROS production, the effect of free radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) was examined. It was found that PAA-induced TNF-α secretion was significantly inhibited by TEMPOL. Our findings indicate that PAA stimulates TNF-α secretion at least in part through ROS production in aortic endothelial cells. The plasma PAA level was reported to be approximately 3.5 mM in end-stage CKD patients, whereas it was <5 μM in healthy subjects; thus, PAA could be involved in the pathological changes of the vasculature in CKD.     

Do reactive oxygen species play a role in myeloid leukemias?

Reactive oxygen species (ROS) are a heterogeneous group of molecules that are generated by mature myeloid cells during innate immune responses, and are also implicated in normal intracellular signaling. Excessive production of ROS (and/or a deficiency in antioxidant pathways) can lead to oxidative stress, a state that has been observed in several hematopoietic malignancies including acute and chronic myeloid leukemias (AML and CML). Currently it is unclear what the cause of oxidative stress might be and whether oxidative stress contributes to the development, progression, or maintenance of these diseases. This article reviews the current evidence suggesting a role for ROS both in normal hematopoiesis and in myeloid leukemogenesis, and discusses the usefulness of therapeutically targeting oxidative stress in myeloid malignancy.     

Reactive oxygen species: Are they important for haematopoiesis?

The production of reactive oxygen species (ROS) has traditionally been related to deleterious effects for cells. However, it is now widely accepted that ROS can play an important role in regulating cellular signalling and gene expression. NADPH oxidase ROS production seems to be especially important in this regard. Some lines of evidence suggest that ROS may be important modulators of cell differentiation, including haematopoietic differentiation, in both physiologic and pathologic conditions. Here we shall review how ROS can regulate cell signalling and gene expression. We shall also focus on the importance of ROS for haematopoietic stem cell (HSC) biology and for haematopoietic differentiation. We shall review the involvement of ROS and NADPH oxidases in cancer, and in particular what is known about the relationship between ROS and haematological malignancies. Finally, we shall discuss the use of ROS as cancer therapeutic targets.     

Peripheral vascular disease and hypertension: a forgotten association?

Peripheral vascular disease (PVD) is associated with a high cardiovascular morbidity and mortality. Intermittent claudication is the most common symptomatic manifestation of PVD, but is also an important predictor of cardiovascular death, increasing it by three-fold, and increasing all-cause mortality by two to five-fold. Hypertension is a common and important risk factor for vascular disorders, including PVD. Of hypertensives at presentation, about 2-5% have intermittent claudication, with this prevalence increasing with age. Similarly, 35-55% of patients with PVD at presentation also have hypertension. Patients who suffer from hypertension with PVD have a greatly increased risk of myocardial infarction and stroke. Apart from the epidemiological associations, hypertension contributes to the pathogenesis of atherosclerosis, the basic underlying pathological process underlying PVD. Hypertension, in common with PVD, is associated with abnormalities of haemostasis and lipids, leading to an increased atherothrombotic state. Nevertheless, none of the large antihypertensive treatment trials have adequately addressed whether a reduction in blood pressure causes a decrease in PVD incidence. There is therefore an obvious need for such outcome studies, especially since the two conditions are commonly encountered together.     

Alzheimer disease as a vascular disorder: Where do mitochondria fit?

Although the precise culprit in the etiopathogenesis of Alzheimer disease (AD) is still obscure, defective mitochondria functioning has been proposed to be an upstream event in AD. Mitochondria fulfill a number of essential cellular functions, and it is recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal and vascular homeostasis. Extensive research in postmortem brain tissue from AD subjects, and AD animal and cellular models revealed that mitochondria undergo multiple malfunctions during the course of this disease. The present review summarizes the current views on how mitochondria are implicated in both AD-related neuronal and cerebrovascular degeneration. The understanding of the mitochondrial mechanisms underlying AD pathology is critical to design more effective strategies to halt or delay disease progression.     

Inflammation and vascular disease: the role of C-reactive protein

Inflammation is an important component of active atherosclerotic disease.C-reactive protein (CRP)is a non-specific inflammatory marker that is increased in inflammatory conditions.Newer more sensitive assays(high sensitivity CRP) can detect the low levels of inflammation associated with vascular disease.CRP levels cangive further risk assessment to individuals beyond predictions from traditional risk factors.This measurement is mostuseful in helping to discriminate risk in intermediate risk patients such as metabolic syndrome patients.Exercise andweight loss have been shown to significantly lower CRP levels.Lipid lowering therapies,especially with the statinclass of medications,also lower CRP levels.A reduction in inflammation may be an important component of plaquestabilization and contribute to cardiovascular risk reduction.(J Geriatr Cardiol 2004;1:17-20.)     

Fibrinogen--marker or mediator of vascular disease?

Fibrinogen plays a key role in platelet aggregation, the final step of the coagulation cascade, i.e. the formation of fibrin, and it is a major determinant of plasma viscosity and erythrocyte aggregation. It is both constitutively expressed and inducible during an acute phase reaction. Increased plasma fibrinogen levels are associated with an increased risk of coronary heart disease and myocardial infarction. The question as to whether fibrinogen is only a marker of the inflammatory process involved in atherosclerosis or a mediator, i.e. a pathogenic factor, has not yet been answered. Human in vivo studies do not permit a conclusive answer to this question. If it is a pathogenic factor, fibrinogen lowering would be a therapeutic option. Selective fibrinogen-lowering agents do not exist however. All agents that lower fibrinogen also have other cardiovascular effects such as a decrease in cholesterol or inflammation. Newer information stems from molecular biology. Polymorphisms in the human fibrinogen gene with higher fibrinogen levels do not increase the risk for myocardial infarction. Fibrinogen knockout mice crossed with an atherosclerosis-susceptible strain (apoprotein E null mice) did not show a decreased extent of atherosclerosis despite the absence of fibrinogen, and a mouse strain over-expressing fibrinogen did not show an increased degree of atherosclerosis. Thus, fibrinogen seems to be a marker rather than a mediator of vascular disease, which would make selective fibrinogen lowering a useless preventive or therapeutic strategy.     

Effect of AndoSan™ on expression of adhesion molecules and production of reactive oxygen species in human monocytes and granulocytes in vivo

Abstract

Background. Oral intake (60 ml daily) over 12 days in eight healthy volunteers of an immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM (AndoSan^?)), reduced the monocyte and granulocyte release of mainly proinflammatory cytokines in vivo, suggesting an anti-inflammatory effect. In this foremost in vivo study, the aim was to examine the effect of such AndoSan^? consumption on the expression of adhesion molecules CD11b, CD11c and CD62L and production of reactive oxygen species (ROS) in leukocytes. Methodology/Principal findings. As shown by flow cytometry, there was a significant increase of CD62L expression on monocytes and granulocytes from before (day 0) compared with 12 days after daily AndoSan^? consumption. However, only minor alterations and no clear trend in the expression of CD11b and CD11c were detected. Intracellular ROS (mainly superoxide ion) were significantly reduced in these cells from days 0 to 12. Conclusions/Significance. These results support that oral intake of AndoSan^? exhibits an anti-inflammatory effect in humans in vivo.     

Effect of AndoSan(™) on expression of adhesion molecules and production of reactive oxygen species in human monocytes and granulocytes in vivo

Abstract Background. Oral intake (60 ml daily) over 12 days in eight healthy volunteers of an immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM (AndoSan(?))), reduced the monocyte and granulocyte release of mainly proinflammatory cytokines in vivo, suggesting an anti-inflammatory effect. In this foremost in vivo study, the aim was to examine the effect of such AndoSan(?) consumption on the expression of adhesion molecules CD11b, CD11c and CD62L and production of reactive oxygen species (ROS) in leukocytes. Methodology/Principal findings. As shown by flow cytometry, there was a significant increase of CD62L expression on monocytes and granulocytes from before (day 0) compared with 12 days after daily AndoSan(?) consumption. However, only minor alterations and no clear trend in the expression of CD11b and CD11c were detected. Intracellular ROS (mainly superoxide ion) were significantly reduced in these cells from days 0 to 12. Conclusions/Significance. These results support that oral intake of AndoSan(?) exhibits an anti-inflammatory effect in humans in vivo.