Papers by Petros Moustardas
Εισαγωγή: Η αθηρωμάτωση αποτελεί μια πάθηση του αρτηριακού τοιχώματος με εξαιρετικά μεγάλη νοσηρό... more Εισαγωγή: Η αθηρωμάτωση αποτελεί μια πάθηση του αρτηριακού τοιχώματος με εξαιρετικά μεγάλη νοσηρότητα και θνητότητα. Στόχος των παρεμβάσεων αντιμετώπισής της αποτελεί πλέον εκτός του μετριασμού του στενωτικού της χαρακτήρα, η σταθεροποίηση των αθηρωματικών πλακών, που με τη ρήξη τους μπορούν να προκαλέσουν πληθώρα καρδιαγγειακών συμβαμάτων. Η ασταθήςαθηρωματική πλάκα χαρακτηρίζεται μεταξύ άλλων από λεπτή ινώδη κάψα,μειωμένες συγκεντρώσεις των εξωκυττάριων συνδετικών πρωτεϊνών (κολλαγόνου και ελαστίνης), κι εκτεταμένη φλεγμονώδη αντίδραση. Η λύση του κολλαγόνου και της ελαστίνης αποδυναμώνει την αθηρωματική πλάκα, και καταλύεται από συγκεκριμένα πρωτεολυτικά ένζυμα, τις μεταλλοπρωτεϊνάσες (MMPs), οι οποίες παράγονται κυρίως από τα φλεγμονώδη κύτταρα (μακροφάγα, αφρώδη κύτταρα) και τα λεία μυϊκά κύτταρα της αθηρωματικής περιοχής. Υπάρχουν ισχυρές ενδείξεις ότι οι MMPsκαι οι αναστολείς τους (TIMPs) βρίσκονται σε μια λεπτή ισορροπία που καθορίζει σε μεγάλο βαθμό την κλινική έκβαση της νόσου. Οι στατίνες, που αποδεδειγμένα ασκούν αθηροπροστατευτικό ρόλο μέσω της μείωσης της χοληστερόλης στο αίμα, πιστεύεται τελευταία ότι ασκούν επιπλέον προστασία μέσω της ρύθμισης μονοπατιών σήμανσης που ελέγχουν τη φλεγμονώδη αντίδραση και επηρεάζουν την έκφραση και λειτουργία των MMPs και των αναστολέων τους. Η συστηματική, μακροχρόνια άσκηση είναι γνωστό ότι συμβάλλει στη μείωση της καρδιαγγειακής νοσηρότητας και θνητότητας.Η τροποποίηση των κλασσικών παραγόντων καρδιαγγειακού κινδύνου μπορεί μόνο εν μέρει να εξηγήσει τα ευεργετικά αποτελέσματα της άσκησης οδηγώντας τους ερευνητές να αναζητήσουν επιπλέον αντιαθηρογόνες δράσεις της, μεταξύ άλλων και της τροποποίησης της έκφρασης και λειτουργίας των MMPs και των TIMPs.Σκοπός: Αντικείμενο της παρούσας διδακτορικής διατριβής ήταν η διερεύνηση της επίδρασης δύο θεραπευτικών στρατηγικών έναντι της αθηρωμάτωσης, της χορήγησης ατορβαστατίνης και της συστηματικής άσκησης, αλλά και του συνδυασμού τους, στη λειτουργία των MMPs και των αναστολέων τους και η συσχέτιση των επιδράσεων αυτών με την εξέλιξη της αθηρωματικής νόσου, όπως αυτή προσδιορίζεται από το μέγεθος και την σταθερότητα των αθηρωματικών αλλοιώσεων.Πειραματικός σχεδιασμός: Προοπτική, τυχαιοποιημένη, ελεγχόμενη μελέτη παρέμβασης. Τοποθεσία: Κέντρο Πειραματικής Χειρουργικής, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών. Πειραματόζωα: Αρσενικοί μύες με ομόζυγη έλλειψη της απολιποπρωτεϊνης Ε(ApoE-/- C57BL/6J knockout mice).Μέθοδος: Την 8η εβδομάδα ηλικίας τους οι μύες τυχαιοποιήθηκαν στις παρακάτω ομάδες: α) Ομάδα ελέγχου αθηρωμάτωσης (CO, n=10), β) Ομάδα χορήγησης ατορβαστατίνης. (ΑΤ, n=10) γ) Ομάδα άσκησης (EX, n=10). δ) Ομάδα συνδυασμένης παρέμβασης ατορβαστατίνης και άσκησης (AT+EX, n=10). Σε όλες τις ομάδες χορηγήθηκε ειδική αθηρογόνος τροφή, με υψηλή περιεκτικότητα σε λιπαρά, για 24 εβδομάδες. Την 16η πειραματική εβδομάδα, ξεκίνησαν οι θεραπευτικές παρεμβάσεις στις ομάδες πλην τηs CO. Στους μύες της ομάδας AT χορηγήθηκε ατορβαστατίνη10mg/Kgr βάρους/ημέρα μέχρι το τέλος της μελέτης. Οι μύες της ομάδας EXυποβλήθηκαν σε πρόγραμμα εκγύμνασης σε ειδικό κυλιόμενο τάπητα μέχρι το πέρας της μελέτης, και οι μύες της ομάδας AT+EX έλαβαν ατορβαστατίνη ομοίως με τους μύες της ομάδας AT και ταυτόχρονα ακολούθησαν πρόγραμμα άσκησης ομοίως με τους μύες της ομάδας EX. Με το τέλος της μελέτης ακολούθησε ευθανασία των μυών. Έγινε λήψη του αορτικού τόξου των μυών προς έγκλειση σε παραφίνη και τομές μικροσκοπίας, και συντήρηση σε βαθιά κατάψυξη της θωρακικής αορτής. Με ιστολογική ανάλυση προσδιορίστηκε το εμβαδό του αγγειακού αυλού και των αθηρωματικών πλακών, και ο βαθμός στένωσης του αυλού κατά μήκος τους αορτικού τόξου. Επιπλέον, με ιστοχημικές και ανοσοϊστοχημικές μεθόδους προσδιορίστηκε το ποσοστό της επιφάνειας της αθηρωματικής πλάκας με θετική χρώση για κολλαγόνο,ελαστίνη, μακροφάγα, λεία μυϊκά κύτταρα, ΜΜΡ-2, ΜΜΡ-3, ΜΜΡ-8, ΜΜΡ-9,ΤΙΜΡ-1, ΤΙΜΡ-2 και TIMP-3. Αιμοληψίες έγιναν σε όλους τους μύες κατά την έναρξη της μελέτης, μετά την ανάπτυξη αθηρωμάτωσης (16η εβδομάδα) και κατά τη λήξη της μελέτης και προσδιορίστηκαν τα επίπεδα της γλυκόζης, της ολικής χοληστερόλης, των τριγλυκεριδίων, της ΜΜΡ-2, της ΜΜΡ-3, της ΜΜΡ-8, της MMP-9, του ΤΙΜΡ-1, του TIMP-2 και του TIMP-3 στο αίμα. Τα τμήματα της θωρακικής αορτής αναλύθηκαν με ζυμογραφία για προσδιορισμό της ενεργού/ανασταλτικής δράσης της MMP-2, της MMP-9, του TIMP-1 και του TIMP-2.Αποτελέσματα: Και οι δύο θεραπευτικές παρεμβάσεις επιβράδυναν την εξέλιξη της αθηρωματικής πλάκας. Αυτό εκφράστηκε ως μειωμένη έκταση του αθηρώματος στις ομάδες που έλαβαν ατορβαστατίνη, και ως μειωμένος βαθμός στένωσης σε όλες τις ομάδες παρέμβασης. Επιπλέον, οι δύο θεραπευτικές παρεμβάσεις εμφάνισαν συνέργεια επιτυγχάνοντας σημαντικά καλύτερα αποτελέσματα στην ομάδα συνδυασμένης παρέμβασης. Όλες οι παρεμβάσεις απέτυχαν να διαφοροποιήσουν τις ομάδες σε σχέση με την απώλεια βάρους και τη γλυκόζη αίματος, ενώ μόνο η χορήγηση ατορβαστατίνης πέτυχε μέτριου βαθμού μείωση των λιπιδίων του αίματος.Οι αθηρωματικές…
Frontiers in Immunology, Mar 22, 2019
Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocr... more Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity. Methods: In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate). Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice. Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.
Frontiers in Immunology, Jul 7, 2021
Introduction: The purpose of this study was to identify differentially expressed proteins in sali... more Introduction: The purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj5 knockout mouse model for Sjögren's syndrome and to elucidate possible mechanisms for the morbid phenotype development. At the same time, we describe for the first time the sexual dimorphism of the murine submandibular salivary gland at the proteome level. Methods: We performed Liquid Chromatography/Mass Spectrometry in salivary gland tissues from both sexes of ERdj5 knockout and 129SV wildtype mice. The resulting list of proteins was evaluated with bioinformatic analysis and selected proteins were validated by western blot and immunohistochemistry and further analyzed at the transcription level by qRT-PCR. Results: We identified 88 deregulated proteins in females, and 55 in males in wildtype vs knockout comparisons. In both sexes, Kallikrein 1b22 was highly upregulated (fold change>25, ANOVA p<0.0001), while all other proteases of this family were either downregulated or not significantly affected by the genotype. Bioinformatic analysis revealed a possible connection with the downregulated NGF that was further validated by independent methods. Concurrently, we identified 416 proteins that were significantly different in the salivary gland proteome of wildtype female vs male mice and highlighted pathways that could be driving the strong female bias of the pathology. Conclusion: Our research provides a list of novel targets and supports the involvement of an NGF-mediating proteolytic deregulation pathway as a focus point towards the better understanding of the underlying mechanism of Sjögren's syndrome.
Cells, Feb 14, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Molecular and Cellular Endocrinology, 2015
Nephrin, a cell surface signaling receptor, regulates podocyte function in health and disease. We... more Nephrin, a cell surface signaling receptor, regulates podocyte function in health and disease. We study the role of nephrin in β-cell survival signaling. We report that in mouse islet β-cells and the mouse pancreatic beta-cell line (βTC-6 cells) nephrin is associated and partly co-localized with PI3-kinase. Incubation of cells with functional anti-nephrin antibodies induced nephrin clustering at the plasma membrane, nephrin phosphorylation and recruitment of PI3-kinase to nephrin thus resulting in increased PI3Kdependent Akt phosphorylation and augmented phosphorylation/inhibition of pro-apoptotic Bad and FoxO. Nephrin silencing abolished Akt activation and increased susceptibility of cells to apoptosis. High glucose impaired nephrin signaling, increased nephrin internalization and up-regulated PKCα expression. Interestingly, a marked decrease in nephrin expression and phosphorylated Akt was observed in pancreatic islets of db/db lepr−/− diabetic mice. Our findings revealed that nephrin is involved in β-cell survival and suggest that glucose-induced changes in nephrin signaling may contribute to gradual pancreatic β-cell loss in type 2 diabetes.
European Journal of Histochemistry, Mar 25, 2013
Physical exercise is the cornerstone of cardiovascular disease treatment. The present study inves... more Physical exercise is the cornerstone of cardiovascular disease treatment. The present study investigated whether exercise training affects atherosclerotic plaque composition through the modification of inflammatoryrelated pathways in apolipoprotein E knockout (apoE-/-) mice with diabetic atherosclerosis. Forty-five male apoE-/mice were randomized into three equivalent (n=15) groups: control (CO), sedentary (SED), and exercise (EX). Diabetes was induced by streptozotocin administration. High-fat diet was administered to all groups for 12 weeks. Afterwards, CO mice were euthanatized, while the sedentary and exercise groups continued high-fat diet for 6 additional weeks. Exercising mice followed an exercise program on motorizedtreadmill (5 times/week, 60 min/session). Then, blood samples and atherosclerotic plaques in the aortic root were examined. A considerable (P<0.001) regression of the atherosclerotic lesions was observed in the exercise group (180.339±75.613¥10 3 μm 2) compared to the control (325.485±72.302¥10 3 μm 2) and sedentary (340.188±159.108¥10 3 μm 2) groups. We found decreased macrophages, matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-8 and interleukin-6 (IL-6) concentrations (P<0.05) in the atherosclerotic plaques of the exercise group. Compared to both control and sedentary groups, exercise training significantly increased collagen (P<0.05), elastin (P<0.001), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) (P<0.001) content in the atherosclerotic plaques. Those effects paralleled with increased fibrous cap thickness and less internal elastic lamina ruptures after exercise training (P<0.05), while bodyweight and lipid parameters did not significantly change. Plasma MMP-2 and MMP-3 concentrations in atherosclerotic tissues followed a similar trend. From our study we can conclude that exercise training reduces and stabilizes atherosclerotic lesions in apoE-/mice with diabetic atherosclerosis. A favorable modification of the inflammatory regulators seems to explain those beneficial effects.
Εισαγωγή: Η αθηρωμάτωση αποτελεί μια πάθηση του αρτηριακού τοιχώματος με εξαιρετικά μεγάλη νοσηρό... more Εισαγωγή: Η αθηρωμάτωση αποτελεί μια πάθηση του αρτηριακού τοιχώματος με εξαιρετικά μεγάλη νοσηρότητα και θνητότητα. Στόχος των παρεμβάσεων αντιμετώπισής της αποτελεί πλέον εκτός του μετριασμού του στενωτικού της χαρακτήρα, η σταθεροποίηση των αθηρωματικών πλακών, που με τη ρήξη τους μπορούν να προκαλέσουν πληθώρα καρδιαγγειακών συμβαμάτων. Η ασταθήςαθηρωματική πλάκα χαρακτηρίζεται μεταξύ άλλων από λεπτή ινώδη κάψα,μειωμένες συγκεντρώσεις των εξωκυττάριων συνδετικών πρωτεϊνών (κολλαγόνου και ελαστίνης), κι εκτεταμένη φλεγμονώδη αντίδραση. Η λύση του κολλαγόνου και της ελαστίνης αποδυναμώνει την αθηρωματική πλάκα, και καταλύεται από συγκεκριμένα πρωτεολυτικά ένζυμα, τις μεταλλοπρωτεϊνάσες (MMPs), οι οποίες παράγονται κυρίως από τα φλεγμονώδη κύτταρα (μακροφάγα, αφρώδη κύτταρα) και τα λεία μυϊκά κύτταρα της αθηρωματικής περιοχής. Υπάρχουν ισχυρές ενδείξεις ότι οι MMPsκαι οι αναστολείς τους (TIMPs) βρίσκονται σε μια λεπτή ισορροπία που καθορίζει σε μεγάλο βαθμό την κλινική έκβαση της ν...
Cells
Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transductio... more Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Once activated through phosphorylation, these MAPKs in turn phosphorylate and activate transcription factors present either in the cytoplasm or in the nucleus, leading to the expression of target genes and, as a consequence, they elicit various biological responses. The aim of this work is to provide a comprehensive review focusing on the roles of MAPK signaling pathways in ocular pathophysiology and the potential to influence these for the treatment of eye diseases. We summarize the current knowledge of identified MAPK-targeting compounds in the context of ocular diseases such as macular degeneration, cataract, glaucoma and keratopathy, but also in rare ocular diseases where the cell differentiation, proliferation or migration are defective. Potential therapeutic interventions are also discussed. Additio...
Frontiers in Immunology
BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease consid... more BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.MethodsAnti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral a...
Introduction: Atherosclerosis is a disease of the arterial wall with high levels ofmorbidity and ... more Introduction: Atherosclerosis is a disease of the arterial wall with high levels ofmorbidity and mortality. Modern therapeutic interventions aim towards both theattenuation of the lumen stenosis as well as the stabilization of the atheromatousplaque and the avoidance of its rupture, which is the cause of the majority ofcardiovascular events. The unstable plaque can be identified by its thin fibrous cap, alesser amount of extracellular connective proteins (collagen and elastin) and extensiveinflammation. The cleavage of collagen and elastin weakens the atheromatous plaque,and is mediated by specific proteolytic molecules, the matrix metalloproteinases(MMPs), which are mostly produced by inflammatory cells (macrophages, foam cells)and the Smooth Muscle Cells within the atheroma. Accumulating evidence pointtowards the fact that the MMPs and their tissue inhibitors (TIMPs) are involved in adelicate balance, which in great part defines the clinical outcome of the disease.Statins, that ar...
Atherosclerosis Supplements, 2010
Atherosclerosis Supplements 11, no. 2 (2010) 17-108 Poster Presentations stepwise regression anal... more Atherosclerosis Supplements 11, no. 2 (2010) 17-108 Poster Presentations stepwise regression analysis, we demonstrated that Nt-proBNP but not hsCRP level was related to Gensin score of severity of coronary artery stenosis in acute coronary syndrome. Conclusion: Nt-proBNP but not hsCRP level is related to severity of coronary artery stenosis in patients in acute coronary syndrome.
Atherosclerosis Supplements, 2010
Atherosclerosis Supplements, 2010
Background: Some modern angioplasty techniques generally just manipulate the form of the plaque. ... more Background: Some modern angioplasty techniques generally just manipulate the form of the plaque. Objective: We designed it to compare two nanobiotechniques of atherodestruction. Methods: A total of 27 white transgenic swines were assigned to the three groups (silica-gold nanoshells with near-infrared irradiation, lentivirus, and saline control). The stroma-specified lentivirus vector was constructed on the basis of long-term fibroblasts cell culture. An ultrasound-mediated microbubbles system has used for the delivery into carotid arteries. The primary combined outcome was the plaque volume (PV) and the atherothrombosis rate. Results: A change of the PV (mm 3 ; on data of IVUS) immediately after the laser irradiation/in 3 months in the group with using of nanoshells (1st group) was 18.1%/34.4% (p < 0.01 for all comparisons [FAC]), and in the group with stroma ablation reached 11.6%/44.5% (p < 0.05 FAC), and in the saline control assessed as 2.9%/4.3% (p < 0.01 as compared with another groups). There were some cases of atherothrombosis (3 cases) but in the nanoshell group only. The histological analysis has confirmed the 'burning' effect of nanophotodestruction with multiple ruptures, necrosis, and consequent possible functional insufficiency of vessel. In the toxin ablation group we have seen only a degradation of adventitia with signs of the plaque rebuilding, revascularization and degradation of the plaque nucleus. Conclusions: The toxin ablation technique with viral vectors is more effective as a tool for the angioplasty with more high level of safety opening new opportunities for the following studies and reflex a clinical relevance of this idea.
Regulatory Peptides, 2012
Objectives: Pulse wave velocity (PWV) constitutes a valid index of arterial stiffness osteoproteg... more Objectives: Pulse wave velocity (PWV) constitutes a valid index of arterial stiffness osteoprotegerin (OPG) and osteopontin (OPN) which are well-established vascular calcification inhibitors, highly correlated with inflammation, and cardiovascular events incidence. We investigated the association of PWV with the aforementioned novel biomarkers in patients with abdominal aortic aneurysm (AAA). Methods: We enrolled 108 men with AAA (AAA group) candidates for endovascular repair. We excluded patients with Marfan syndrome or other collagen-related disorders. Forty-one age-matched men, with stable coronary artery disease (CAD), but without AAA, served as controls (CO group). PWV, clinical parameters and serum levels of osteoprotegerin (OPG), osteopontin (OPN), interleukin-6 (IL-6) and IL-10 were determined. Results: With the exception of higher smoking rate and the lower statin's usage in the AAA group, there were non-significant differences in the rest of demographic and clinical parameters (p>0.05). We found significantly higher levels of PWV in AAA than CO group (12.99± 3.75 m/s vs 10.03± 1.57 m/s, p b 0.001). In parallel, serum OPG, OPN, IL-6 levels were considerably increased, while IL-10 levels were downregulated (pb 0.001) in AAA group. PWV positively correlated with mean blood pressure, OPG concentrations and AAA diameter in univariate and multivariate analysis (R 2 =0.498, p =0.008). Finally, age and OPG remained independent determinants of AAA presence in the whole study cohort. Conclusions: Arterial stiffness, circulating vascular calcification inhibitors and inflammatory mediators seem to be significantly upregulated in patients with AAA. An independent association of PWV with mean blood pressure, OPG and AAA diameter is of clinical importance which requires further investigation.
European Journal of Cardiovascular Prevention & Rehabilitation, 2007
Physical exercise is the cornerstone of cardiovascular disease treatment. The present study inves... more Physical exercise is the cornerstone of cardiovascular disease treatment. The present study investigated whether exercise training affects atherosclerotic plaque composition through the modification of inflammatoryrelated pathways in apolipoprotein E knockout (apoE-/-) mice with diabetic atherosclerosis. Forty-five male apoE-/mice were randomized into three equivalent (n=15) groups: control (CO), sedentary (SED), and exercise (EX). Diabetes was induced by streptozotocin administration. High-fat diet was administered to all groups for 12 weeks. Afterwards, CO mice were euthanatized, while the sedentary and exercise groups continued high-fat diet for 6 additional weeks. Exercising mice followed an exercise program on motorizedtreadmill (5 times/week, 60 min/session). Then, blood samples and atherosclerotic plaques in the aortic root were examined. A considerable (P<0.001) regression of the atherosclerotic lesions was observed in the exercise group (180.339±75.613¥10 3 μm 2) compared to the control (325.485±72.302¥10 3 μm 2) and sedentary (340.188±159.108¥10 3 μm 2) groups. We found decreased macrophages, matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-8 and interleukin-6 (IL-6) concentrations (P<0.05) in the atherosclerotic plaques of the exercise group. Compared to both control and sedentary groups, exercise training significantly increased collagen (P<0.05), elastin (P<0.001), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) (P<0.001) content in the atherosclerotic plaques. Those effects paralleled with increased fibrous cap thickness and less internal elastic lamina ruptures after exercise training (P<0.05), while bodyweight and lipid parameters did not significantly change. Plasma MMP-2 and MMP-3 concentrations in atherosclerotic tissues followed a similar trend. From our study we can conclude that exercise training reduces and stabilizes atherosclerotic lesions in apoE-/mice with diabetic atherosclerosis. A favorable modification of the inflammatory regulators seems to explain those beneficial effects.
Cardiovascular Drugs and Therapy, 2012
Purpose Dabigatran etexilate (DE) constitutes a novel, direct thrombin inhibitor. Regarding the a... more Purpose Dabigatran etexilate (DE) constitutes a novel, direct thrombin inhibitor. Regarding the association of thrombin with atherogenesis, we assessed the effects of DE on the development and stability of atherosclerotic lesions in apolipoprotein-E deficient (ApoE−/−) mice. Materials-methods Fifty male ApoE−/− mice were randomized to receive western-type diet either supplemented with DE 7.5 mg DE/g chow) (DE-group, n025) or matching placebo as control (CO-group, n025) for 12 weeks. After this period, all mice underwent carotid artery injury with ferric chloride and the time to thrombotic total occlusion (TTO) was measured. Then, mice were euthanatized and each aortic arch was analyzed for the mean plaque area, the content of macrophages, elastin, collagen, nuclear factor kappaB (NFκB), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1). Results DE-group showed significantly longer TTO compared to CO-group (8.9±2.3 min vs 3.5±1.1 min, p<0.001) and the mean plaque area was smaller in DE-group than CO-group (441.00±160.01×10 3 μm 2 vs 132.12± 32.17× 10 3 μm 2 , p<0.001). Atherosclerotic lesions derived from DE-treated mice showed increased collagen (p00.043) and elastin (p00.031) content, thicker fibrous caps (p<0.001) and reduced number of internal elastic lamina ruptures per mm of arterial girth (p<0.001) when compared to COgroup. Notably, DE treatment seemed to promote plaque stability possibly by reducing concentrations of NFκB, VCAM-1, macrophages and MMP-9 and increasing TIMP-1 within atherosclerotic lesions (p<0.05). Conclusions DE attenuates arterial thrombosis, reduces lesion size and may promote plaque stability in ApoE−/− mice. The plaque-stabilizing effects of chronic thrombin inhibition might be the result of the favorable modification of inflammatory mechanisms.
Journal of Vascular Research, 2011
Aim: To investigate the effects of exercise on atherosclerotic plaque composition, the concentrat... more Aim: To investigate the effects of exercise on atherosclerotic plaque composition, the concentration of matrix metalloproteinases (MMPs) in the atherosclerotic plaque and the systemic circulation. Methods: Ninety apolipoprotein E-deficient (apoE–/–) mice (45 male) were randomized to the following groups (n = 15 each): control male/female; sedentary male/female; exercise male/female. Mice were kept on a 16-week high-fat diet. Subsequently, the control groups were sacrificed, while the rest of the animals were placed on a normal diet for 6 more weeks. During the latter period, the exercise groups were trained daily on treadmill. At the end of the study, mice were euthanized, and blood samples as well as aortic root specimens were obtained. Results: Compared to control and sedentary animals, exercise training reduced atherosclerotic plaques (–30%; p < 0.01) and increased elastin and collagen content in both genders (p < 0.05). Body weight or lipid profile did not change significa...
Aim: This study aimed to investigate the effects of combined atorvastatin and exercise treatment ... more Aim: This study aimed to investigate the effects of combined atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in apolipoproteinE (apoE) knockout mice. Methods: Forty male, apoE2/2 mice were fed a high-fat diet for 16 weeks. Thereafter, while maintained on high-fat diet, they were randomized into four (n = 10) groups for 8 additional weeks: Group CO: Control. Group AT: Atorvastatin treatment (10 mg/Kg/day). Group EX: Exercise-training on treadmill. Group AT+EX: Atorvastatin and simultaneous exercise training. At the study’s end, plasma cholesterol levels, lipids and triglycerides were measured, along with the circulating concentrations of matrix-metalloproteinases (MMP-2,3,8,9) and their inhibitors (TIMP-1,2,3). Plaque area and the relative concentrations of collagen, elastin, macrophages, smooth muscle cells, MMP-2,3,8,9 and TIMP-1,2,3 within plaques were determined. Lastly, MMP activity was assessed in the aortic arch. Results: All...
Frontiers in Immunology
Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocr... more Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity. Methods: In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate). Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice. Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.
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Papers by Petros Moustardas