Wim Martinet

University of Antwerp, Antwerpen, Flemish, Belgium

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Publications (139)679.76 Total impact

  • Atherosclerosis 07/2015; 241(1):e15. DOI:10.1016/j.atherosclerosis.2015.04.069 · 3.97 Impact Factor
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    ABSTRACT: Peripheral blood (PB) admixture should be minimized during numerical and functional, as well as cytokinetic analysis of bone marrow (BM) aspirates for research purposes. Therefore, purity assessment of the BM aspirate should be performed in advance. We investigated whether bone matrix vesicle (BMV)-bound bone alkaline phosphatase (ALP) could serve as a marker for the purity of BM aspirates. Total ALP activity was significantly higher in BM serum (97 (176-124) U/L, median (range)) compared to PB serum (63 (52-73) U/L, p<0.001). Agarose gel electrophoresis showed a unique bone ALP fraction in BM, which was absent in PB. Native polyacrylamide gel electrophoresis revealed the high molecular weight of this fraction, corresponding with membrane-bound ALP from bone matrix vesicles (BMV), as evidenced by electron microscopy. A serial PB admixture experiment of bone cylinder supernatant samples, rich in BMV-bound ALP, confirmed the sensitivity of this proposed quality assessment method. Furthermore, a BMV ALP fraction of ≥15 % is suggested as cut-off value for minimal BM quality. Also, the BM purity declines rapidly with larger aspirated BM volumes. The exclusive presence of BMV-bound ALP in BM could serve as a novel marker to assess purity of BM aspirates. Copyright © 2015. Published by Elsevier B.V.
    Clinica chimica acta; international journal of clinical chemistry 04/2015; 446. DOI:10.1016/j.cca.2015.04.013 · 2.76 Impact Factor
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    ABSTRACT: L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein.
    PLoS ONE 03/2015; 10(3):e0121634. DOI:10.1371/journal.pone.0121634 · 3.53 Impact Factor
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    ABSTRACT: We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoE(-/-)Fbn1(C1039G+/-)) develop accelerated atherosclerosis with enhanced inflammation, atherosclerotic plaque rupture, myocardial infarction and sudden death. In the brain, fibrillin-1 functions as an attachment protein in the basement membrane, providing structural support to the blood-brain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the blood cerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoE(-/-) (n=61) and ApoE(-/-)Fbn1(C1039G+/-) (n=73) mice were fed a Western-type diet (WD). After 14 weeks WD, a significantly higher permeability of the BBB was observed in ApoE(-/-)Fbn1(C1039G+/-) mice compared to age-matched ApoE(-/-) mice. This was accompanied by leukocyte infiltration, enhanced expression of pro-inflammatory cytokines, matrix metalloproteinases and transforming growth factor-β, and by decreased expression of tight junction proteins claudin-5 and occludin. After 20 weeks WD, 83% of ApoE(-/-)Fbn1(C1039G+/-) mice showed xanthomas in the brain, compared to 23% of their ApoE(-/-) littermates. Xanthomas were mainly located in fibrillin-1 rich regions, such as the choroid plexus and the neocortex. Our findings demonstrate that dysfunctional fibrillin-1 impairs BBB/BCSFB integrity, facilitating peripheral leukocyte infiltration, which further degrades the BBB/BCSFB. As a consequence, lipoproteins can enter the brain, resulting in accelerated formation of xanthomas. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 03/2015; 295. DOI:10.1016/j.neuroscience.2015.03.023 · 3.33 Impact Factor
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    ABSTRACT: Autophagy is a reparative, life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. Growing evidence reveals that basal autophagy is an essential in vivo process mediating proper vascular function. Moreover, autophagy is stimulated by many stress-related stimuli in the arterial wall to protect endothelial cells and smooth muscle cells against cell death and the initiation of vascular disease, in particular atherosclerosis. Basal autophagy is atheroprotective during early atherosclerosis but becomes dysfunctional in advanced atherosclerotic plaques. Little is known about autophagy in other vascular disorders, such as aneurysm formation, arterial aging, vascular stiffness, and chronic venous disease, even though autophagy is often impaired. This finding highlights the need for pharmacological interventions with compounds that stimulate the prosurvival effects of autophagy in the vasculature. A large number of animal studies and clinical trials have indicated that oral or stent-based delivery of the autophagy inducer rapamycin or derivatives thereof, collectively known as rapalogs, effectively inhibit the basic mechanisms that control growth and destabilization of atherosclerotic plaques. Other autophagy-inducing drugs, such as spermidine or add-on therapy with widely used antiatherogenic compounds, including statins and metformin, are potentially useful to prevent vascular disease with minimal adverse effects. © 2015 American Heart Association, Inc.
    Circulation Research 01/2015; 116(3):468-479. DOI:10.1161/CIRCRESAHA.116.303804 · 11.09 Impact Factor
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    ABSTRACT: Bevacizumab is the first anti-angiogenic agent approved for the treatment of metastatic colorectal cancer. The need for patient selection before initiating therapy necessitates the study of various proteins expressed in metastatic colorectal cancer tissue as candidate predictive markers. Immunohistochemistry is a valuable, commonly available and cost-effective method to assess predictive biomarkers. However, it is subject to variations and therefore requires rigorous protocol standardizations. Furthermore, validated quantification methodologies to study these angiogenic elements have to be applied. Based on their function in tumor angiogenesis and their relation to the mechanism of action of bevacizumab, protein markers were divided in four groups: VEGF A-signaling proteins; other relevant angiogenesis factors; factors regarding the tumor microenvironment and tumor intrinsic markers. Conceivably, nimbly selecting a small but relevant group of therapy-guided patients by the appropriate combination of predictive biomarkers may confer great value to this angiogenic inhibitor.
    Expert Review of Molecular Diagnostics 01/2015; 15(3):1-16. DOI:10.1586/14737159.2015.993972 · 4.27 Impact Factor
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    ABSTRACT: Autophagy is an evolutionary preserved process that prevents the accumulation of unwanted cytosolic material through the formation of autophagosomes. Although autophagy has been studied extensively to understand its function in normal physiology, the role of vascular smooth muscle cell (VSMC) autophagy in calcium mobilization and contraction remains poorly understood. Recent evidence shows that autophagy is involved in controlling contractile function and calcium homeostasis in certain cell types. Therefore, autophagy might also regulate contractile capacity and calcium mobilizing pathways in VSMCs. Contractility (organ chambers) and calcium homeostasis (myograph) were investigated in aortic segments of 3.5 month old mice containing a SMC-specific deletion of Atg7 (Atg7(fl/fl) SM22α-Cre(+)) and in segments of corresponding controls (Atg7(fl/fl) SM22α-Cre(+)). Our results indicate that voltage-gated calcium channels (VGCCs) of Atg7(fl/fl) SM22α-Cre(+) VSMCs were more sensitive to depolarization, independent of changes in resting membrane potential. Contractions elicited with K(+) (50 mM) or the VGCC agonist BAY K8644 (100 µM) were significantly higher due to increased VGCC expression and activity. Interestingly, the sarcoplasmic reticulum (SR) of Atg7(fl/fl) SM22α-Cre(+) VSMCs was enlarged, which combined with increased SERCA2 expression and higher store-operated calcium entry promoted inositol triphosphate-mediated contractions of Atg7(fl/fl) SM22α-Cre(+) segments and maximized the calcium storing capacity of the SR. Moreover, decreased plasma membrane Ca(2+)-ATPase (PMCA) expression in Atg7(fl/fl) SM22α-Cre(+) VSMCs hampered calcium extrusion to the extracellular environment. Overall, our study indicates that defective autophagy in VSMCs leads to an imbalance between calcium release/influx and calcium re-uptake/extrusion, resulting in higher basal calcium concentrations and significant effects on vascular reactivity. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 01/2015; 308(6):ajpheart.00659.2014. DOI:10.1152/ajpheart.00659.2014 · 4.01 Impact Factor
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    ABSTRACT: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder, characterized by extensive mineralization of connective tissues and fragmentation of elastin fibres. PXE patients may sporadically suffer from severe cardiovascular complications caused by accelerated atherosclerosis. Consistent with this finding, recent evidence suggests that elastin fragmentation in arteries of atherosclerotic mice leads to unstable plaques and human-like complications such as myocardial infarction, stroke and sudden death. Because Abcc6-/- mice manifest the human features of PXE including the fragmentation of elastin fibres, Abcc6-/- mice were crossbred with ApoE-/- mice to investigate the level of plaque formation and potential complications. ApoE-/- and ApoE-/- Abcc6-/- mice were fed a Western-type diet (WD) for 25 weeks to induce plaque formation.WD-fed animals showed neither signs of neurological dysfunction nor sudden death. Cardiac function of ApoE-/- Abcc6-/- mice, as assessed by echocardiography, was not different from ApoE-/- control mice. Histochemical analysis did not reveal elastin fragmentation or pronounced mineral deposition in the vessel wall. Plaques from the proximal ascending aorta and brachiocephalic artery of ApoE-/- Abcc6-/- mice were similar in size and composition as compared to ApoE-/- mice. Moreover, en face oil red O stainings of the aortic arch and descending thoracic aorta did not reveal enhanced plaque formation in ApoE-/- Abcc6-/- mice as compared to ApoE-/-controls. ApoE-/-Abcc6-/- mice do not represent an adequate model of accelerated atherosclerosis and therefore are not useful to study atherosclerosis-related complications as observed in PXE patients.
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    ABSTRACT: Apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE(-/-) Fbn1(C1039G+/-) mice on WD for 20weeks (n=21). ApoE(-/-) mice on WD (n=24) and ApoE(-/-) Fbn1(C1039G+/-) mice on normal diet (ND, n=21) served as controls. Starting from 10weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13weeks of diet to study spatial learning. At the end of the experiment (20weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12weeks onward, gait analysis of ApoE(-/-) Fbn1(C1039G+/-) mice on WD revealed a progressive increase in track width as compared to ApoE(-/-) mice on WD and ApoE(-/-) Fbn1(C1039G+/-) mice on ND (at 20weeks: 29.8±0.6mm vs. 25.8±0.4mm and 26.0±0.5mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE(-/-) Fbn1(C1039G+/-) mice on WD at 18 and 20weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE(-/-) Fbn1(C1039G+/-) mice on WD. Furthermore, the parietal cortex of ApoE(-/-) Fbn1(C1039G+/-) mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE(-/-) Fbn1(C1039G+/-) mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice. Copyright © 2014. Published by Elsevier Inc.
    Physiology & Behavior 11/2014; 139. DOI:10.1016/j.physbeh.2014.11.047 · 3.03 Impact Factor
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    ABSTRACT: L-type calcium channel blockers (LCCBs) reduce blood pressure more effectively in hypertensive than in normotensive subjects and are more effective in vascular smooth muscle (VSM) than in cardiac muscle. This has been explained by the depolarized resting potential of VSM in comparison with heart muscle cells and during hypertension, because both favor the “high affinity” inactivated state of the L-type calcium channel (LCC). Depolarized resting potentials, however, also increase Ca2+ influx via window, non-inactivating LCC. The present study investigated whether these channels can be effectively blocked by nifedipine, verapamil or diltiazem, as representatives of different LCCB classes. C57Bl6 mouse aortic segments were depolarized by 50 mM K+ to attain similar degree of inactivation. The depolarization evoked biphasic contractions with the slow force component displaying higher sensitivity to LCCBs than the fast component. Removal of the fast force component increased, whereas stimulation of Ca2+ influx with the dihydropyridine BAY K8644, a structural analog of nifedipine, decreased the efficacy of the LCCBs. Addition of LCCBs during the contraction caused concentration-dependent relaxation, which was independent of the presence of a fast force component, but still showed lower sensitivity in the presence of BAY K8644. Our data suggest that steady-state contractions by depolarization with 50 mM K+ are completely due to window Ca2+ influx, which is preferentially inhibited by LCCBs. Furthermore, results point to interactions between the LCCB receptors and Ca2+ ions or BAY K8644. The high affinity for open, non-inactivating LCC may play a dominant role in the anti-hypertensive effects of LCCBs.
    European Journal of Pharmacology 09/2014; 738:170–178. DOI:10.1016/j.ejphar.2014.05.036 · 2.68 Impact Factor
  • Atherosclerosis 08/2014; 235(2):e116-e117. DOI:10.1016/j.atherosclerosis.2014.05.318 · 3.97 Impact Factor
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    ABSTRACT: Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients. The potential role of autophagy in disease is increasingly recognised and investigated in the last decade. Nowadays it is commonly accepted that autophagy plays a role in the hepatic lipid metabolism. Hence, dysfunction of autophagy may be an underlying cause of non-alcoholic fatty liver disease. However, controversy of the exact role of autophagy in the lipid metabolism exists: some publications report a lipolytic function of autophagy, whereas others claim a lipogenic function. This review aims to give an update of the present knowledge on autophagy in the hepatic lipid metabolism, hepatic insulin resistance, steatohepatitis and hepatic fibrogenesis.
    World Journal of Gastroenterology 06/2014; 20(23):7325-7338. DOI:10.3748/wjg.v20.i23.7325 · 2.43 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S10-S11. DOI:10.1016/S0168-8278(14)60026-X · 10.40 Impact Factor
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    ABSTRACT: Statins are currently able to stabilize atherosclerotic plaques by lowering plasma cholesterol and pleiotropic effects, but a residual risk for atherosclerotic disease remains. Therefore, effective prevention of atherosclerosis and treatment of its complications is still a major clinical challenge. A large body of evidence indicates that mammalian target of rapamycin (mTOR) inhibitors such as rapamycin or everolimus have pleiotropic anti-atherosclerotic effects so that these drugs can be used as add-on therapy to prevent or delay the pathogenesis of atherosclerosis. Moreover, bioresorbable scaffolds eluting everolimus trigger a healing process in the vessel wall, both in pigs and humans, that results in late lumen enlargement and plaque regression. At present, this phenomenon of atheroregression is poorly understood. However, given that mTOR inhibitors suppress cell proliferation and trigger autophagy, a cellular survival pathway and a process linked to cholesterol efflux, we hypothesize that these compounds can inhibit (or reverse) the basic mechanisms that control plaque growth and destabilization. Unfortunately, adverse effects associated with mTOR inhibitors such as dyslipidemia and hyperglycemia have recently been identified. Dyslipidemia is manageable via statin treatment, while the anti-diabetic drug metformin would prevent hyperglycemia. Because metformin has beneficial macrovascular effects, this drug in combination with an mTOR inhibitor might have significant promise to treat patients with unstable plaques. Moreover, both statins and metformin are known to inhibit mTOR via AMPK activation so that they would fully exploit the beneficial effects of mTOR inhibition in atherosclerosis.
    Atherosclerosis 04/2014; 233(2):601–607. DOI:10.1016/j.atherosclerosis.2014.01.040 · 3.97 Impact Factor
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    ABSTRACT: There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death. Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke. Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.
    European Heart Journal 02/2014; 36(17). DOI:10.1093/eurheartj/ehu041 · 14.72 Impact Factor
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    ABSTRACT: Autophagy is a well-conserved lysosomal degradation pathway that plays a major role in both oncogenesis and tumor progression. Transmission electron microscopy (TEM) as well as immunohistochemistry are indispensable tools for the evaluation of autophagy in situ. Here, we describe an optimized protocol for the study of autophagic vacuoles by TEM and elaborate on the immunohistochemical detection of microtubule-associated protein 1 light chain (MAP1LC3, best known as LC3), which is currently considered as one of the most reliable markers of the autophagic process. The advantages, potential pitfalls, and limitations of these methods, as well as their value in the field of autophagy and oncometabolism research are discussed. Overall, we recommend a combined use of different techniques including TEM, immunohistochemistry, and molecular approaches (such as immunoblotting) for the unambiguous detection of autophagy in malignant as well as in normal tissues.
    Methods in Enzymology 01/2014; 543:89-114. DOI:10.1016/B978-0-12-801329-8.00005-2 · 2.19 Impact Factor
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    ABSTRACT: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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    ABSTRACT: Despite recent scientific and technological advances, cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of heart pathologies. However, the precise role of autophagy in these contexts remains obscure owing to its multifarious actions. Here, we review recently derived insights regarding the role of autophagy in multiple manifestations of cardiac plasticity and disease.
    Autophagy 08/2013; 9(10). DOI:10.4161/auto.25969 · 11.42 Impact Factor
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    ABSTRACT: Atherosclerosis is a chronic inflammatory disease of large and middle-sized blood vessels, and the leading cause of death among adults in the Western world. Recent evidence suggests that several molecular and cellular mechanisms play an important role in atherosclerosis and plaque progression. One of these mechanisms includes autophagy, a subcellular process for elimination of damaged organelles and protein aggregates via lysosomes. According to in vitro observations, the autophagic machinery is stimulated by several stress-related stimuli inside plaques, such as oxidized lipids, endoplasmic reticulum stress, hypoxia, nutrient deprivation, and inflammation. Although its role in atherosclerosis has not yet been fully established, a growing body of evidence indicates that autophagy has a protective function in atherosclerosis. It stimulates cholesterol efflux and reduces foam cell formation. Moreover, it prevents apoptosis by removing oxidatively damaged hyperpolarized mitochondria before reactive oxygen species production and cytochrome c release. Another important recent finding is that macrophage autophagy plays an essential role in delaying lesion progression by suppressing inflammasome activation. Interestingly, excessive everolimus-induced autophagy leads to selective macrophage death, and is a promising plaque-stabilizing strategy. Overall, autophagy seems to be a major player in atherosclerosis, but further research has to be performed to fully clarify its role in this disease.
    AUTOPHAGY: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, 1 edited by M. A. Hayat, 07/2013: chapter 6: pages 79-90; Elsevier., ISBN: 978-0-12-405530-8
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    ABSTRACT: Atherosclerosis is a chronic inflammatory disorder of the arterial wall leading to coronary artery disease, stroke, and peripheral arterial disease. Along with the discovery of dipeptidyl peptidase 4 (DPP4) as a therapeutic target in type 2 diabetes, a role for DPP4 in atherosclerosis is emerging. However, until now the expression and role of other DPPs such as DPP8 and DPP9 in atherosclerosis is completely unknown. In the present study, we first investigated DPP expression in human atherosclerotic plaques. DPP4 could only be observed in endothelial cells of plaque neovessels in half of the specimens. In contrast, DPP8 and DPP9 were abundantly present in macrophage-rich regions of plaques. We then focused on DPP expression and function in macrophage differentiation, activation and apoptosis. DPP8/9 was responsible for most of the DPP activity in macrophages. During monocyte to macrophage differentiation, DPP9 was upregulated both in pro-inflammatory M1 (3.7 ± 0.3-fold increase) and anti-inflammatory M2 macrophages (3.7 ± 0.4-fold increase) whereas DPP8 expression remained unchanged. Inhibition of DPP8/9 activity with compound 1G244 reduced activation of M1 macrophages (IL-6 88 ± 16 vs. 146 ± 19 pg/ml; TNFα 3.8 ± 1.0 vs. 6.6 ± 1.9 ng/ml in treated vs. untreated cells), but not of M2 macrophages. Likewise, DPP9 silencing reduced TNFα and IL-6 secretion, pointing to a DPP9-mediated effect of the inhibitor. DPP8/9 inhibition also enhanced macrophage apoptosis (15 ± 4 vs. 7 ± 3 % in untreated cells). Because pro-inflammatory macrophages play a key role in atherogenesis, plaque rupture and subsequent infarction, DPP9 inhibition might provide interesting therapeutic prospects in reducing atherosclerosis and/or in the prevention of plaque rupture.
    Archiv für Kreislaufforschung 05/2013; 108(3):350. DOI:10.1007/s00395-013-0350-4 · 5.96 Impact Factor