Human neutrophil peptides upregulate expression of COX-2 and endothelin-1 by inducing oxidative stress

Polymorphonuclear leukocytes (PMNs) play an important role during inflammation in cardiovascular diseases. Human neutrophil peptides (HNPs) are released from PMN granules upon activation and are conventionally involved in microbial killing. Recent studies suggested that HNPs may be involved in the pathogenesis of vascular abnormality by modulating inflammatory responses and vascular tone. Since HNPs directly interact with endothelium upon release from PMNs in the circulation, we tested the hypothesis that the stimulation with HNPs of endothelial cells modulates the expression of vasoactive by-products through altering cyclooxygenase (COX) activity. When human umbilical vein endothelial cells were stimulated with purified HNPs, we observed a time- and dose-dependent increase in the expression of COX-2, whereas COX-1 levels remained unchanged. Despite an increased expression of COX-2 at the protein level, HNPs did not significantly enhance the COX-2 activity, thus the production of the prostaglandin PGI2. HNPs significantly induced the release of endothelin-1 (ET-1) as well as the formation of nitrotyrosine. The HNP-induced COX-2 and ET-1 production was attenuated by the treatment with the oxygen free radical scavenger N-acetyl-L-cysteine and the inhibitors of p38 MAPK and NF-kappaB, respectively. The angiontensin II pathway did not seem to be involved in the HNP-induced upregulation of COX-2 and ET-1 since the use of the angiotensin-converting enzyme inhibitor enalapril had no effect in this context. In conclusion, HNP may play an important role in the pathogenesis of inflammatory cardiovascular diseases by activating endothelial cells to produce vasoactive by-products as a result of oxidative stress.     

Candidate gene polymorphisms and the 9p21 locus in acute coronary syndromes

It is now widely accepted that the classic environmental risk factors for atherosclerosis only partly explain the incidence of coronary artery disease and the development of acute coronary syndromes. Therefore, genetic factors that vary among human populations seem to be involved in the clinical manifestations of such patients. Substantial data suggest that a significant proportion of genetic polymorphisms involved in endothelial function, inflammation, lipid metabolism, thrombosis and fibrinolysis are often present in patients with acute coronary syndromes. In particular, a common variant on chromosome 9p21 was recently identified to affect the risk of myocardial infarction. Here, we review the progress of candidate gene studies and genome-wide association studies in identifying the genetic bases of complex cardiovascular diseases such as acute coronary syndromes.     

A role for acute-phase serum amyloid A and high-density lipoprotein in oxidative stress,endothelial dysfunction and atherosclerosis

Abstract

The acute-phase protein serum amyloid A (SAA) is a clinically useful marker of inflammation and associates strongly with increased risk of cardiovascular events. Chronically elevated SAA concentrations may contribute to physiological processes that lead to atherosclerosis, including endothelial dysfunction, an early and predictive event in the development of cardiovascular disease. Accumulating data suggest that SAA can be a direct mediator in the development and progression of atherogenesis and atherothrombosis. SAA may affect key events underlying acute coronary syndromes, including cholesterol transport, contribute to endothelial dysfunction, promote thrombosis, and enhance leukocyte trafficking and activation. This review summarizes the evidence supporting a role for SAA as a potential regulator of inflammation and endothelial dysfunction, which underlie the adverse outcomes that complicate coronary artery disease. The findings suggest that novel therapeutic strategies to reduce SAA levels and/or oppose the actions of SAA may have beneficial effects in patients with coronary artery disease.     

Cholesterol lowering and the vessel wall: new insights and future perspectives.

The basis for most acute coronary events is either rupture or fissuring of unstable atherosclerotic plaques with subsequent thrombosis leading to coronary artery occlusion. The development of atherosclerotic plaques takes several decades, but the mechanical features determining its stability and the risk of rupture can change very rapidly depending on a number of internal factors. Unstable plaques have a large lipid core, a thin overlying fibrous cap and an abundance of inflammatory cells. The most important factor determining the plaque stability is the plasma level of atherogenic LDL particles. Increased levels of these particles cause endothelial dysfunction with impaired vasodilatation capacity and prevalence of vasoconstriction, maintain inflammatory infiltration of the plaque, impair the strength of the fibrous cap and facilitate aggregation and coagulation. Effective lowering of plasma cholesterol by pharmacological and non-pharmacological means can revert most of these processes and increase the plaque's mechanical stability within several hours to days. Lipid lowering therapy can therefore decrease the risk of acute coronary events within a very short space of time. Thus a radical decrease in lipid levels, along with modification of other risk factors, may become the cornerstone for treatment of acute coronary syndromes, in addition to being an effective treatment in primary and secondary prevention of coronary heart disease (CHD).     

Platelet-activating factor acetylhydrolase: is it good or bad for you?

PURPOSE OF REVIEW: Although findings obtained from various studies are inconclusive in determining whether plasma platelet-activating factor acetylhydrolase, or lipoprotein-associated phospholipase A2, plays a proatherogenic or antiatherogenic role in atherosclerosis, many recent reviews appear to favor it as a risk factor for coronary artery disease. To provide a contrasting view, this review focuses on the enzyme's antiatherogenic and antiinflammatory properties. RECENT FINDINGS: A recent report demonstrates that plasma platelet-activating factor acetylhydrolase activity increases in men and women with stable angina or acute coronary syndromes, supporting previously published data that plasma levels of the protein are independently and positively associated with the risk of coronary artery disease. In contrast, at least four lines of evidence indicate that the enzyme has strong antiatherogenic properties: (1) it inhibits the effects of LDL oxidation, (2) genetic deficiency of plasma levels constitutes a risk factor for vascular diseases including atherosclerosis, (3) adenoviral transfer of the protein reduces atherosclerosis in apolipoprotein E-deficient mice, and (4) pretreatment of an electronegative LDL subfraction isolated from hypercholesterolemic human plasma with a recombinant platelet-activating factor acetylhydrolase completely abolishes the proapoptotic effects of the electronegative LDL on vascular endothelial cells. Additionally, treatment with the recombinant product reduced mortality from severe sepsis in a phase IIb clinical trial. In an animal study, transfection of tumor cells with platelet-activating factor acetylhydrolase inhibited tumor growth at the site of implantation. SUMMARY: Plasma platelet-activating factor acetylhydrolase becomes progressively activated as atherosclerosis progresses, but lines of evidence indicate that the enzyme possesses potent antiatherogenic and antiinflammatory properties. This raises the question of whether increased activity is a cause or a result of atherosclerosis and, consequently, whether inhibiting the enzyme's activities may decelerate or accelerate the progress of the disease.     

炎症与动脉粥样硬化及冠状动脉疾病的关系

炎症在冠状动脉疾病和其他动脉粥样硬化性疾病中起着重要作用.在动脉粥样硬化早期病变处存在大量的免疫细胞,它们所分泌的一系列细胞因子加速病变的进程,激活炎症反应导致急性冠脉综合症的发生.动脉粥样硬化,是冠状动脉疾病的主要病因,是一种炎性疾病,炎症因子参与到免疫反应过程中,使得动脉壁处的病变得以发生、蔓延和活化.     

Human neutrophil defensins increase neutrophil uptake of influenza A virus and bacteria and modify virus-induced respiratory burst responses

Human neutrophil peptides (HNPs) are released from granules of neutrophils in response to various activating stimuli and they participate in the killing of bacteria and the stimulation of various inflammatory responses. HNPs also inhibit infectivity of enveloped viruses, including influenza A virus (IAV). In this study, we demonstrate that HNPs increase the uptake of IAV and bacteria by neutrophils. The dimeric HNPs also induced aggregation of IAV and bacterial particles, which may, in part, explain their ability to increase uptake. HNPs did not increase neutrophil respiratory burst responses to IAV. We have recently demonstrated direct interactions of HNPs with surfactant protein D (SP-D), another important effector of innate immunity and antimicrobial host defense. Although HNPs did not alter SP-D-dependent uptake of IAV, they counteracted the ability of SP-D to increase IAV-induced neutrophil H2O2 generation. Our studies reveal previously unappreciated functional effects of HNPs, expand our understanding of the antiviral properties of HNPs, and suggest important interactions between collectins and HNPs in the host response to viruses and bacteria.     

Inflammatory markers and coronary heart disease

PURPOSE OF REVIEW: Despite changes in lifestyle and the use of effective pharmacologic interventions to lower cholesterol levels, coronary heart disease remains the major cause of morbidity and mortality in the developed world. Cholesterol screening fails to identify almost 50% of those individuals who will present with acute coronary syndromes. Recent evidence from laboratory and prospective clinical studies demonstrates that atherosclerosis is not simply a disease of lipid deposition, but rather is an inflammatory process with highly specific cellular and molecular responses. The clinical utility of inflammatory markers has been examined in a variety of atherothrombotic diseases. Because C-reactive protein is highly stable in stored frozen samples, and automated and robust analytical systems for its measurement are available, it has become the most widely examined inflammatory marker. RECENT FINDINGS: C-reactive protein has consistently been shown to be a useful prognostic indicator in acute coronary syndromes and is a strong predictor of future coronary events in apparently healthy individuals. In addition, C-reactive protein can identify individuals with normal lipid levels who are at increased risk for future coronary events. Because drugs such as aspirin and statins reduce inflammatory risk, C-reactive protein has the potential to guide the use of these therapies in high-risk individuals for primary prevention. SUMMARY: C-reactive protein may have a role in global risk assessment for primary prevention and in targeting those patients who will benefit from anti-inflammatory therapies. In addition, it may also be a good prognostic indicator in patients with acute coronary syndromes.     

Regulated expression of endothelial cell-derived lipase

A lipoprotein lipase-like gene was recently cloned from endothelial cells. In vitro functional experiments have suggested that this endothelial-derived lipase (EDL) has phospholipase activity, and preliminary in vivo studies have suggested a role in the regulation of high-density lipoprotein metabolism. To investigate local control of lipase activity and lipid metabolism in the blood vessel wall, we have examined the regulation of EDL expression in cultured human umbilical vein and coronary artery endothelial cells. EDL mRNA levels were upregulated in both cell types by inflammatory cytokines implicated in vascular disease etiology, including TNF-alpha and IL-1beta. In addition, both fluid shear stress and cyclic stretch were found to increase the EDL mRNA levels in these cultured cells. This highly regulated expression of EDL in vascular endothelial cells suggests that this recently identified lipase is intricately involved in modulating vessel wall lipid metabolism and may play a role in vascular diseases such as atherosclerosis.     

Enzymology and molecular biology of prokaryotic sulfite oxidation

The intracellular bacterial pathogen Chlamydia pneumoniae causes respiratory tract infection and has been associated with atherosclerosis and coronary artery disease. Since atherosclerosis is a progressive disease and is considered to be a chronic inflammation of the artery vessel wall, the interaction of C. pneumoniae with cells of the vasculature that can result in a local inflammatory response is of paramount importance. In this essay we review the pathophysiology of atherosclerosis in the context of C. pneumoniae infection and present an integrated model that includes the involvement of C. pneumoniae in all stages of atherogenesis including initiation, inflammation, fibrous plaque formation, plaque rupture and thrombosis. We hypothesize that acute and persistent infection of professional immune cells (T-cells, monocytes and macrophages) and non-immune cells (endothelial cells and smooth muscle cells) contributes to a sustained inflammatory response mediated by extensive cellular 'crosstalk' and numerous cytokines/chemokines. This cascade of inflammatory mediators may contribute to cellular dysfunction and tissue remodelling of the arterial intima. An improved understanding of the precise mechanism(s) of C. pneumoniae involvement in atherogenesis may help resolve the question of causality however, at the present time, we interpret the data as favoring a contributory rather than a causal role. Future research directed at the discovery of chlamydial virulence factors necessary for intracellular survival and subsequent alterations in host cell gene expression including signalling pathways may be important for the design of future clinical trials.     

Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence

PURPOSE OF REVIEW: Review the cellular mechanisms and clinical evidence for the use of statins in patients with unstable coronary syndromes. RECENT FINDINGS: Clinical trials of statin therapy in acute coronary syndromes demonstrate a rapid improvement in endothelial function, improved perfusion to ischemic myocardium, and an early reduction in cardiovascular events. The early benefit of statin therapy is related to a combination of molecular mechanisms that involve the oxidized LDL receptor (LOX-1), endothelial localized nitric oxide synthase, inflammatory cytokines, interstitial collagenases, and tissue factor expression. In human atheroma, 3 months' use of statin (pravastatin) therapy reduced the content of oxidized LDL, inflammatory cells (macrophage, T cells) infiltrates, and improved plaque stability by increasing the collagen content of the fibrous cap. SUMMARY: The antiatherothrombotic effects of statin therapy appear to have important clinical relevance to patients with impaired myocardial perfusion and acute coronary syndrome.     

High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease

PURPOSE OF REVIEW: Low HDL-cholesterol, diabetes mellitus and elevated C-reactive protein as well as various inflammatory diseases are risk factors for coronary heart disease. Both diabetes mellitus and inflammation decrease HDL-cholesterol. We summarize recent findings on the mechanisms underlying low HDL-cholesterol in diabetes and inflammation, as well as on novel functions of HDL that may protect not only from atherosclerosis but also from diabetes mellitus and inflammation-induced organ damage. RECENT FINDINGS: Elevated levels of non-esterified fatty acids and disturbed insulin action contribute to low HDL-cholesterol in diabetes mellitus by modifying lipolysis, apolipoprotein A-I production, as well as the activities of adenosine triphosphate-binding cassette transporter A1 and lipid transfer. Inflammation causes low HDL-cholesterol by increasing the activities of endothelial lipase and soluble phospholipase A2 and by replacing apolipoprotein A-I in HDL with serum amyloid A. HDL and lysosphingolipids therein have been identified as activators of the protein kinase Akt, which in turn is a regulator of apoptosis in beta-cells, endothelial cells, and smooth muscle cells, as well as a regulator of nitric oxide production and adhesion molecule expression in endothelial cells. SUMMARY: The protective properties of HDL in cytokine production, lipid oxidation, cholesterol efflux and reverse cholesterol transport make HDL a protective agent in inflammation-induced organ damage including diabetes mellitus. However, inflammation and diabetes cause a decrease in HDL-cholesterol concentrations and impair HDL function, placing HDL into the centre of a vicious cycle that may escalate into diabetes mellitus, inflammation-induced organ damage and atherosclerosis.     

Low magnesium and atherosclerosis: an evidence-based link

Several data indicate that magnesium deficiency caused by poor diet and/or errors in its metabolism may be a missing link between diverse cardiovascular risk factors and atherosclerosis. Experimentally induced low plasma levels of magnesium accelerate atherogenesis by increasing LDL concentrations and their oxidative modifications, and by promoting inflammation. In vitro studies have shown that low magnesium determines endothelial dysfunction, the initiating event leading to the formation of the plaque. Moreover, oral magnesium therapy has been shown to improve endothelial function in patients with coronary artery disease.Magnesium, which is an inexpensive, natural and rather safe element, could be useful in preventing atherosclerosis and as an adjuvant therapy in patients with clinical manifestations of the disease.     

Involvement of caveolin-1 and CD36 in native LDL endocytosis by endothelial cells

Atherosclerosis is a lipid disease characterized by accumulation of low density lipoprotein (LDL) in the artery wall. The transport of LDL across the endothelium of coronary artery is an initiating event of atherosclerosis, whose mechanism remains poorly understood. In the last decade, it has been shown that in caveolin-1 (Cav-1) deficient mice, LDL infiltration in aorta wall is decreased and CD36 expression in aortas is down-regulated, leading to regression of atherosclerotic lesions. In the present study, we show that native LDL endocytosis is decreased in endothelial cells deficient in Cav-1 or CD36. We demonstrate that Cav-1 and CD36 interact in caveolae-rich domains by different biochemical approaches. In addition, confocal microscopy reveals some colocalization of Cav-1 with CD36. These findings indicate that caveolae and CD36 are involved in native LDL endocytosis and suggest that CD36 might be a good candidate for the transport of native LDL across the endothelium, an early event in atherosclerosis.     

Low density lipoprotein (LDL), atherosclerosis and antioxidants

A crucial and causative role in the pathogenesis of atherosclerosis is believed to be the oxidative modification of low density lipoprotein (LDL). The oxidation of LDL involves released free radical driven lipid peroxidation. Several lines of evidence support the role of oxidized LDL in atherogenesis. Epidemiologic studies have demonstrated an association between an increased intake of dietary antioxidant vitamins, such as vitamin E and vitamin C and reduced morbidity and mortality from coronary artery diseases. It is thus hypothesized that dietary antioxidants may help prevent the development and progression of atherosclerosis. The oxidation of LDL has been shown to be reduced by antioxidants, and, in animal models, improved antioxidants may offer possibilities for the prevention of atherosclerosis. The results of several on going long randomized intervention trials will provide valuahle information on the efficacy and safety of improved antioxidants in the prevention of atherosclerosis. This review a evaluates current literature involving antioxidants and vascular disease, with a particular focus on the potential mechanisms.     

Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases

Dietary intervention strategies have proven to be an effective means of decreasing several risk factors associated with the development of atherosclerosis. Endothelial cell dysfunction influences vascular inflammation and is involved in promoting the earliest stages of lesion formation. Caveolae are lipid raft microdomains abundant within the plasma membrane of endothelial cells and are responsible for modulating receptor-mediated signal transduction, thus influencing endothelial activation. Caveolae have been implicated in the regulation of enzymes associated with several key signaling pathways capable of determining intracellular redox status. Diet and plasma-derived nutrients may modulate an inflammatory outcome by interacting with and altering caveolae-associated cellular signaling. For example, omega-3 fatty acids and several polyphenolics have been shown to improve endothelial cell function by decreasing the formation of ROS and increasing NO bioavailability, events associated with altered caveolae composition. Thus, nutritional modulation of caveolae-mediated signaling events may provide an opportunity to ameliorate inflammatory signaling pathways capable of promoting the formation of vascular diseases, including atherosclerosis.     

Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor

Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A(4) receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.     

Epigenetic histone acetylation modifiers in vascular remodelling – new targets for therapy in cardiovascular disease

In the past decade, research into cardiovascular diseases, such as atherosclerosis and restenosis, has been focused on the identification of genetic factors that determine disease risk besides clinical risk factors. Many genes in lipid metabolism, vascular homeostasis, haemostasis and inflammation have been found to be related to coronary artery disease1 and the multifactorial nature of the disease suggests a role for many other, yet uninvestigated genes. Previous research from our department has demonstrated the importance of genetics in restenosis after a percutaneous coronary intervention (PCI). Polymorphisms in several inflammatory genes, such as TNFα, eotaxin, CD14, GM-CSF, IL-10, caspase-1, but also noninflammatory genes, such as LPL, stromelysin-1 and the β adrenergic receptor have been found to be associated with the risk of restenosis.2-5 It has become clear, however, that part of the gene-environmental interactions relevant for complex diseases is regulated by epigenetic mechanisms such as histone acetylation and DNA methylation.     

Imaging of coronary atherosclerosis and identification of the vulnerable plaque

Identification of the vulnerable plaque responsible for the occurrence of acute coronary syndromes and acute coronary death is a prerequisite for the stabilisation of this vulnerable plaque. Comprehensive coronary atherosclerosis imaging in clinical practice should involve visualisation of the entire coronary artery tree and characterisation of the plaque, including the three-dimensional morphology of the plaque, encroachment of the plaque on the vessel lumen, the major tissue components of the plaque, remodelling of the vessel and presence of inflammation.Obviously, no single diagnostic modality is available that provides such comprehensive imaging and unfortunately no diagnostic tool is available that unequivocally identifies the vulnerable plaque.The objective of this article is to discuss experience with currently available diagnostic modalities for coronary atherosclerosis imaging. In addition, a number of evolving techniques will be briefly discussed.     

Role of calprotectin in cardiometabolic diseases

Calprotectin represents an interesting peptide known to be involved in the pathophysiology of various inflammatory processes. Being secreted from activated neutrophils and monocytes under various conditions, it can also be found in the extracellular fluids and serve as a biomarker of ongoing inflammation, which property is currently used in the monitoring of inflammatory bowel diseases.Recent studies, however, suggest that calprotectin could serve as an important prognostic factor for cardiovascular and cardiometabolic diseases, since these are occurring on the basis of low-grade chronic inflammation. We assume that calprotectin may represent a useful marker in predicting the course of atherosclerotic process, coronary artery disease and acute coronary syndromes. Our review is focused on the importance of calprotectin in the diagnosis and prognostic stratification in the field of cardiometabolic risk.