1,721,003 research outputs found
INCREASED ENDOPLASMIC RETICULUM STRESS AND NRF2 REPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH STABLE CORONARY ARTERY DISEASE
No full textEndoplasmic reticulum (ER) stress is involved in the pathophysiology of atherosclerosis. Insults interfering with endoplasmic reticulum (ER) function, lead to accumulation of unfolded and misfolded proteins in ER that initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signaling is induced.
We evaluated: 1) the UPR and ER-initiated apoptotic signaling in peripheral blood mononuclear cells (PBMC) of stable coronary artery disease patients (CAD); 2) PBMC content of oxidation products of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC); 3) the possible origin of oxPAPC in PBMC; 4) the expression of nuclear erytroid-related factor 2 (Nrf2)/antioxidant related element (ARE), a cellular defence mechanism.
29 CAD and 28 matched controls were enrolled. Expression of glucose-regulated protein 78 kDa (GRP78/BiP) as representative of UPR, and of C/EBP homologous protein (CHOP) as representative of ER-apoptosis, were significantly higher in CAD than in controls (p<0.01). Concentrations of oxPAPC in PBMC, in plasma and in low density lipoprotein (LDL) resulted significantly higher in CAD than in controls (p<0.01). The oxPAPC in PBMC may derive from circulating ox-LDL. Nrf2/ARE gene expression and circulating and cellular glutathione (GSH) were significantly lower in CAD than in controls (p<0.01). In in vitro studies, increasing amounts of oxPAPC induced a dose-dependent increase of CHOP and apoptosis-related protein expression (p<0.01) and a progressive decrease of Nrf2/ARE gene expression (p<0.01).
In PBMC of CAD patients there is an activation of UPR and of ER-initiated apoptotic signaling, possibly related to abnormal concentration of oxPAPC in PBMC
CIGARETTE SMOKING BLOCKS THE PROTECTIVE EXPRESSION OF Nrf2/ARE PATHWAY IN BLOOD CELLS OF YOUNG HEAVY SMOKERS FAVOURING INFLAMMATION: RELATION WITH ENDOTHELIAL FUNCTION AND CAROTID INTIMA MEDIA THICKNESS
No full textBackground: Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), of
nuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined
an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSH
concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs).
Methods and Results: 52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokers
we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation
products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and in
peripheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showed
impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs
exposed to smokers’ serum but not to non-smokers’ serum we found that oxidative stress increased, whereas nitric oxide
and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamatecysteine
ligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis
that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed
HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in
smokers’ serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant
reduction of HO-1 and GCLC expression induced by oxPAPC in ECs.
Conclusions: In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/
ARE pathway leading to GSH depletion
Progeria, atherosclerosis and clonal hematopoiesis: links and future perspectives
No full textThe main actors of this review are Hutchinson-Gilford progeria syndrome (HGPS) and atherosclerosis. HGPS is a very rare disease with no definitively approved specific drugs. Atherosclerosis is a very common disease with a more consolidated treatment strategy. Nevertheless, common mechanisms are shared by both these diseases, particularly related to inflammation, oxidative and endoplasmic reticulum (ER) stress. Pathways regulated by Nuclear factor E2 related factor (Nrf2), Nuclear factor kappa B (NF-kB) and related to the Unfolded Protein Response (UPR) and ER stress are receiving increasing attention. In HGPS "not omnia" happen(s) "cum tempore", that means that HGPS patients have atherosclerotic complications before their time. The third actor is clonal hematopoiesis: it constitutes a link between ageing and atherosclerosis. This review aims to analyse the current knowledge of atherosclerosis and clonal hematopoiesis in order to suggest therapeutic strategies to correct the timing of the atherosclerosis progression in HGPS. The goal for HGPS is a shift from "not omnia cum tempore" to "omnia cum tempore" in terms of significant lifespan extension by postponing atherosclerosis-related complications
RECENT ACQUISITIONS ABOUT THE ROLE OF ENDOPLASMIC RETICULUM STRESS AND NRF2 SIGNALLING IN CARDIOVASCULAR DISEASES AND IN ATHEROSCLEROTIC PLAQUE VULNERABILITY
No full textInsults interfering with endoplasmic reticulum (ER) function lead to the accumulation of unfolded and misfolded proteins in the ER. An excess of proteins folding in the ER is known as ER stress. This condition initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signalling is induced. This review investigates the role of the inflammatory and oxidative impairment as possible UPR and ER apoptosis inductors in triggering the ER stress response. Moreover, the role of the protective nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE) and the activation of the pro-inflammatory nuclear factor-kappa B (NF-kB) are analysed. The Authors summarize evidence that oxidative stress, inflammation and ER stress are closely entwined phenomena. They are involved in the pathogenesis of different settings of cardiovascular diseases.The Authors' own experiences and current literature data are collected, focusing on three precise topics: atherosclerotic plaque, coronary artery disease and diabetes.The current field of research will provide a platform for study and application to several other conditions in which oxidative stress, ER stress and inflammation are key features. Future studies in this area may identify the most promising molecules to be investigated as common targets for cardiovascular diseases.Insults interfering with endoplasmic reticulum (ER) function lead to the accumulation of unfolded and misfolded proteins in the ER. An excess of proteins folding in the ER is known as ER stress. This condition initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signalling is induced. This review investigates the role of the inflammatory and oxidative impairment as possible UPR and ER apoptosis inductors in triggering the ER stress response. Moreover, the role of the protective nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE) and the activation of the pro-inflammatory nuclear factor-kappa B (NF-kB) are analysed. The Authors summarize evidence that oxidative stress, inflammation and ER stress are closely entwined phenomena. They are involved in the pathogenesis of different settings of cardiovascular diseases.The Authors' own experiences and current literature data are collected, focusing on three precise topics: atherosclerotic plaque, coronary artery disease and diabetes.The current field of research will provide a platform for study and application to several other conditions in which oxidative stress, ER stress and inflammation are key features. Future studies in this area may identify the most promising molecules to be investigated as common targets for cardiovascular diseases
The role of Neutrophil Extracellular Traps in Covid-19: Only an hypothesis or a potential new field of research?
No full textletter to Edito
Unstable Angina: focus on NF-kB, inflammation and possible link to Neutrophil Extracellular Traps
No full textThe Most Severe Paradigm of Early Cardiovascular Disease: Hutchinson-Gilford Progeria. Focus on the Role of Oxidative Stress
No full textOxidative stress (OS) is one of the most frequently recognized causes of ageing. Telomere erosion, defects in the DNA damage response and alterations in the nuclear architecture are also associated with premature ageing. The most severe premature ageing syndrome, Hutchinson-Gilford progeria syndrome (HGPS) is associated with alterations in nuclear shape resulting in the deregulation of lamin A/C. In this review we describe emerging data reporting the role of OS and antioxidant defence in progeroid syndromes focusing on HGPS. We explore precise antioxidant defence mechanisms and related drugs that may create a potential path out of the woods in this disease. Pathways regulated by Nuclear factor E2 related factor (Nrf2), by Nuclear Factor kappa B (NF-kB), and related to the Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) stress are under investigation in HGPS patients for which the goal is a significant lifespan extension in particular by postponing atherosclerosis-related complications
An exploratory look at NETosis in atherosclerosis
No full textCurrent evidence suggests the likelihood of a link between venous thromboembolism (VTE) and atherosclerosis, although they have been traditionally considered as different pathological entities. The contribution of neutrophils to human atherogenesis has been underestimated, if compared to their contribution established in VTE. This is due to the major importance attributed to macrophages in plaque destabilization. Nevertheless, the role of neutrophils in atherogenesis deserves increasing attention. In particular, neutrophil extracellular traps (NETs) are net-like chromatin fibres that are released from dying neutrophils. The death of neutrophils with NETs formation is called NETosis. During activation, neutrophils produce reactive oxygen species (ROS), through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The main function of NETs is trapping and killing pathogens. Nevertheless, NETs formation has been observed in various chronic inflammatory diseases, autoimmune diseases, vasculitis, lung diseases, cancer and VTE. Recent studies suggest that NETs formation might contribute also to atherosclerosis progression. New data report the presence of NETs in the luminal portion of human atherosclerotic vessels and coronary specimens obtained from patients after acute myocardial infarction. Programmed death mechanisms in atherosclerosis such as apoptosis, efferocytosis and also NETosis, share common features and triggers. If defective, they can lead the cells to a switch from programmed death to necrosis, resulting in the release of pro-atherogenic factors, accumulation of cell debris and progression of the disease. This review provides evidence on the emerging role of neutrophils focusing on NETosis and oxidative stress burden in orchestrating common mechanisms in atherosclerosis and thrombosis
A Five-Step Vascular Ultrasound Examination in Heart Failure: The First Two Years of the "ABCDE" G-SIUMB Multicenter Study 2018-2022
No full textThe aim of this study is the creation of a 5-step ultrasound examination to evaluate and monitor Heart Failure (HF) patients during hospitalization and follow-up. "ABCDE" is the acronym of an Italian multicentre study composed of a consecutive sample of HF patients admitted from the Emergency to the Internal Medicine/Geriatric Departments of several Italian hospitals. The "ABCDE" score includes the evaluations of A, the Ankle-brachial index (ABI), B, the B-lines, C, the Carotid intima media thickness (CIMT), D, the Diameter of the abdominal aorta and of the inferior cave vein and E, the echocardiographic assessment of the ejection fraction. This paper reports the preliminary results. Up to now, the "ABCDE" multicenter study seems an exciting opportunity to create an integrative ultrasound approach in HF. The definitive confirmation of these preliminary results and the effective usefulness of the "ABCDE" will be available in 2022, at the end of the study
An Exploratory Look at Bicuspid Aortic Valve (Bav) Aortopathy: Focus on Molecular and Cellular Mechanisms
No full textBicuspid aortic valve (BAV) is the most common congenital heart malformation. BAV patients are at increased risk for aortic valve disease (stenosis/regurgitation), infective endocarditis, thrombi formation and, in particular, aortic dilatation, aneurysm and dissection. This review aims at exploring the possible interplay among genetics, extracellular matrix remodeling, abnormal signaling pathways, oxidative stress and inflammation in contributing to BAV-associated aortopathy (BAV-A-A). Novel circulating biomarkers have been proposed as diagnostic tools able to improve risk stratification in BAV-A-A. However, to date, the precise molecular and cellular mechanisms that lead to BAV-A-A remain unknown. Genetic, hemodynamic and cardiovascular risk factors have been implicated in the development and progression of BAV-A-A. Oxidative stress may also play a role, similarly to what observed in atherosclerosis and vulnerable plaque formation. The identification of common pathways between these 2 conditions may provide a platform for future therapeutic solutions
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