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Advanced glycation end products: a spoiler for cardiac function and CASCs transplantation potential?
No full textHart- en vaatziekten zijn de nummer één doodsoorzaak wereldwijd. Bij hartfalen
is het hart niet meer in staat is om voldoende bloed rond te pompen om aan de
energiebehoeftes van het lichaam te voldoen. Dit is een complex proces wat
gekenmerkt wordt door verschillende structurele en functionele veranderingen in
de fysiologie van het hart. Hartfalen kan veroorzaakt worden door een hartinfarct,
hartritmestoornissen, onbehandelde hoge bloeddruk, lekkende hartkleppen of
ziekten van de hartspierwand. De laatste jaren heeft onderzoek aangetoond, dat
versuikerde eiwitten of advanced glycated end products (AGEs) een belangrijke
rol kunnen spelen in het ziekteproces van hartfalen. AGEs zijn gemodificeerde
eiwitten, waaraan een suikergroep zit verankerd. Naarmate we ouder worden,
stapelen deze AGEs zich op doorheen ons lichaam. Ook onze voeding kan een
grote bron zijn van AGEs, wanneer eiwitrijk voedsel wordt gebakken op droge,
hoge temperatuur bijvoorbeeld bij barbecueën, aanstoven of karamelliseren.
Eerder werd al aangetoond, dat kleine AGEs met een laagmoleculair gewicht
cellulaire veranderingen induceren in de hartspiercellen. Ook complexe AGEs met
een hoogmoleculair gewicht (HMW) zijn prominent aanwezig in ons Westers dieet.
We onderzochten daarom in hoofdstuk 1 van deze thesis of HMW-AGEs een
schadelijke invloed hebben op de functionele en morfologische eigenschappen van
hartspiercellen, wat kan leiden tot hartfalen.
Naast hartfalen, zijn ook ischemische hartziekten of hartinfarct (MI), in de
volksmond hartaanval genoemd, verantwoordelijk voor vele sterfgevallen in
België. Tijdens een MI, zal een deel van de hartspier afsterven doordat de
bloedtoevoer door de kransslagaderen naar een deel van de hartspier wordt
onderbroken. De hartspiercellen die op dat moment geen bloedtoevoer krijgen,
zullen irreversibel worden beschadigd. Het is daarom erg belangrijk om de
bloedtoevoer naar het hart snel te herstellen. Het is belangrijk dat deze patiënten
een goede behandeling krijgen omdat MI kan leiden tot het ontstaan van
hartfalen. Het is echter zo dat de behandeling momenteel enkel gericht is op het
bestrijden van de symptomen, aangezien de onderliggende oorzaak (irreversibel
beschadigde hartspiercellen) nog niet aangepakt kan worden. De enige manier
om een MI te genezen, zou het herstellen of vervangen zijn van de beschadigde
hartspiercellen, door nieuwe cellen. Cellulaire therapie met stamcellen biedt daarom vele mogelijkheden. Toch moet er nog veel onderzoek uitgevoerd worden,
voordat stamceltherapie kan worden ingezet als effectieve therapie voor MIpatiënten.
Ook in het ziekteproces van MI spelen versuikerde eiwitten of AGEs een rol. Door
de ontstekingsreactie die optreedt en de overvloed aan stressfactoren na MI,
zullen de concentratie AGEs in het hart toenemen. Als we patiënten in de toekomst
willen behandelen met nieuwe stamceltherapieën, is het daarom belangrijk om de
stamcellen te transplanteren in optimale omstandigheden. In hoofdstuk 2 van
deze thesis werd daarom onderzocht door middel van literatuurstudie of AGEs een
negatieve invloed hebben op verschillende soorten stamcellen. Daarnaast werd in
hoofdstuk 3 onderzocht, of AGEs een effect hebben op een specifiek type
stamcellen (cardiale hartoor stamcellen, geïsoleerd uit hartspierweefsel zelf). Ten
slotte werd in hoofdstuk 4 ook het effect van een anti-AGEs therapie bestudeerd
in combinatie met de transplantatie van deze cardiale stamcellen na MI
THE BEST OF BOTH WORLDS: IN VITRO EVALUATION OF COMBINING TWO STEM CELL TYPES FOR TRUE CARDIAC REPAIR
No full textINTRODUCTION: Bone healing can be augmented by pre-conditioning MSCs (pMSCs) with inflammatory cytokines. Another approach is timely resolution of inflammation using immunomodula-tory cytokines. We investigated the efficacy of pMSC and genetically modified MSCs that over-express IL-4 (IL4-MSCs) on early stage steroid-associated osteonecrosis of the femoral head (ONFH) in rabbits .METHODS: 36 male mature NZW rabbits received methylpred-nisolone acetate (20mg/kgIM) 4 weeks before surgery. There were 6 groups: 1. Core Decompress (CD) alone-a 3 mm drill hole+ injection of:2. hydrogel (HG)-200 ml of hydrogel carrier3. MSCs-1 million rabbit MSCs4. pMSC-LPS (20 mg/ml) + TNFa (20 ng/ml) precondi-tioned MSCs 5. IL4-MSCs-rabbit IL-4 over-expressing MSCs 6. IL4-pMSCs-preconditioned IL-4 over-expressing MSCsEight weeks after surgery, femurs were evaluated by microCT, biomechanical, and his-tological analyses.RESULTS: Bone mineral density (BMD) and bone volume fraction (BVF) increased outside the CD in the pMSC group compared to the CD and MSC groups (p < 0.05). IL4-pMSC group was increased compared to the CD group (p < 0.05). The percentage of empty lacunae in the IL4-MSC group was significantly less than other groups outside the CD (p < 0.05); however, IL4-MSC group had less trabecular bone formation inside the CD. DISCUSSION: pMSC increased new bone formation after CD in ONFH; IL4-MSCs decreased the number of empty lacunae. Immunomodulation of bone healing has the potential to improve bone healing after CD for early stage ONFH; these interventions must be applied in a temporally sensitive fashion
Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity
No full textNew Findings
What is the central question of this study?
Does acute exposure to high molecular weight advanced glycation end products (HMW‐AGEs) alter cardiomyocyte contractile function?
What is the main finding and its importance?
Ventricular cardiomyocytes display reduced Ca2+ influx, resulting in reduced contractile capacity, after acute exposure to HMW‐AGEs, independent of activation of their receptor. Given that HMW‐AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds.
Abstract
Sustained elevated levels of high molecular weight advanced glycation end products (HMW‐AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW‐AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre‐incubated with or without an anti‐RAGE antibody. Unloaded cell shortening and L‐type Ca2+ current amplitude were evaluated in the presence or absence of HMW‐AGEs (200 μg ml−1). Expression of RAGE, c‐Jun N‐terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW‐AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca2+ influx. These alterations were also observed in cardiomyocytes pre‐incubated with anti‐RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW‐AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation.This research was funded by a Bijzonder onderzoeksfonds(BOF)grant from HasseltUniversity (15NI06-BOF
Combining stem cells in myocardial infarction: The road to superior repair?
No full textMyocardial infarction irreversibly destroys millions of cardiomyocytes in the ventricle, making it the leading cause of heart failure worldwide. Over the past two decades , many progenitor and stem cell types were proposed as the ideal candidate to regenerate the heart after injury. The potential of stem cell therapy has been investigated thoroughly in animal and human studies, aiming at cardiac repair by true tissue replacement, by immune modulation, or by the secretion of paracrine factors that stimulate endogenous repair processes. Despite some successful results in animal models, the outcome from clinical trials remains overall disappointing, largely due to the limited stem cell survival and retention after transplantation. Extensive interest was developed regarding the combina-tional use of stem cells and various priming strategies to improve the efficacy of regenerative cell therapy. In this review, we provide a critical discussion of the different stem cell types investigated in preclinical and clinical studies in the field of cardiac repair. Moreover, we give an update on the potential of stem cell combinations as well as preconditioning and explore the future promises of these novel regenerative strategies. Abbreviations: ALDH, aldehyde dehydrogenase; BM, bone marrow; BM-MNC, bone marrow mononuclear cell; CASC, cardiac atrial appendage stem cell; CDC, cardiosphere-derived cell; CPC, cardiac progenitor cell; CVD, cardiovascular disease; Cx43, connexin43; DMOG, dimethyloxalylglycine; EPC, endothelial progenitor cell; EV, extracellular vesicle; hESC, human embryonic stem cell; HIF, hypoxia-inducible factor; HSC, hematopoietic stem cell; iPSC, induced pluripotent stem cell; iPSC-CM, induced pluripotent stem cell-derived cardiomyocyte; Isl-1, islet-1; LAD, left anterior descending; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MI, myocardial infarction; MSC, mesenchymal stem cell; Sca-1, stem cell antigen-1.Fonds Wetenschappelijk Onderzoek, Grant/Award Number: 1154120N; Bijzonder Onderzoeksfonds, Grant/Award Numbers: Universiteit Hasselt 16NI05BOF, Universiteit Hasselt BOF20TT04
Figures were created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http:// smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. This study is supported by an aspirant PhD mandate to H.B. (Grant no. 1154120 N) from the “Research Foundation‐Flanders” (“Fonds Wetenschappelijk Onderzoek Vlaanderen”—FWO) as well as a Special Research Fund (BOF) of Hasselt University (Reference number BOF20TT04) to A.B. L.E. benefits from a “Bijzonder Onderzoeksfonds” (BOF) grant from Hasselt University (Grant no. 16NI05BOF)
The Impact of Advanced Glycation End-Products (AGEs) on Proliferation and Apoptosis of Primary Stem Cells: A Systematic Review
No full textStem cell-based regenerative therapies hold great promises to treat a wide spectrum of diseases. However, stem cell engraftment and survival are still challenging due to an unfavorable transplantation environment. Advanced glycation end-products (AGEs) can contribute to the generation of these harmful conditions. AGEs are a heterogeneous group of glycated products, nonenzymatically formed when proteins and/or lipids become glycated and oxidized. Our typical Western diet as well as cigarettes contain high AGEs content. AGEs are also endogenously formed in our body and accumulate with senescence and in pathological situations. Whether AGEs have an impact on stem cell viability in regenerative medicine remains unclear, and research on the effect of AGEs on stem cell proliferation and apoptosis is still ongoing. Therefore, this systematic review provides a clear overview of the effects of glycated proteins on cell viability in various types of primary isolated stem cells used in regenerative medicine.Figures were created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. This work was supported by a Bijzonder onderzoeksfonds (BOF) grant from Hasselt University (grant number: 16NI05BOF). HB benefits from an aspirant PhD mandate (grant number: 1154120N) of the `Research Foundation-Flanders' (fonds voor wetenschappelijk onderzoek (FWO)). PG is also supported by the FWO (grant numbers: 12U7718N and 1502120N).Bito, V (corresponding author), Hasselt Univ, Biomed BIOMED Res Inst, Agoralaan Bldg C, B-3590 Diepenbeek, Belgium.
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Pyridoxamine Protects Against Cardiotoxicity After Doxorubicin Chemotherapy
No full textIntroduction: Although doxorubicin (DOX) is an efficient anthracycline agent used to treat cancer, it induces cardiotoxicity and mortality in cancer survivors. Cardioprotection is inadequate. The vitamin B6-derivative pyridoxamine (PM) has shown to be cardioprotective in diverse cardiac diseases. Whether PM offers cardioprotection after DOX treatment is unknown. We hypothesized that PM limits cardiac impairment after DOX treatment by reducing cardiac fibrosis and inflammation.
Methods: Female Sprague Dawley rats were weekly treated with 2 mg/kg DOX or saline IV for 8 weeks. At DOX treatment onset, 2 extra groups received PM (1 g/L) via the drinking water. Echocardiographic (4D) and hemodynamic parameters were assessed at week 8, together with plasma BNP. PCR analysis was performed on left ventricular tissue to evaluate fibrosis and inflammation. Data were compared using 1-way ANOVA, Kruskal-Wallis test or 2-way ANOVA with post-hoc tests as appropriate.
Results: As shown in Table 1, cardiac impairment by DOX was prevented by PM. In addition, DOX significantly increased the expression of fibrosis markers, such as TGFβ (0.29 ± 0.02 vs. 0.69 ± 0.09 a.u., p<0.0001), LOX (0.055 ± 0.002 vs. 0.590 ± 0.174 a.u., p<0.01), collagen type 1 (0.21 ± 0.02 vs. 0.62 ± 0.11 a.u., p<0.001) and interstitial collagen (4.6 ± 0.3 vs. 7.7 ± 0.6%, p<0.001). DOX also increased the inflammation marker IL-6 (0.13 ± 0.03 vs. 0.73 ± 0.13 a.u., p<0.01). PM treatment significantly lowered all these parameters (p<0001, p<0.001, p<0.01, p<0.01 and p<0.01 respectively).
Conclusions: In conclusion, our data show that DOX causes dilated cardiomyopathy with reduced ejection fraction, accompanied by cardiac fibrosis and myocarditis. As PM limits this adverse phenotype, it could be a novel cardioprotective strategy for DOX-treated cancer patients
Glycolaldehyde-modified proteins cause adverse functional and structural aortic remodeling leading to cardiac pressure overload
No full textGrowing evidence supports the role of advanced glycation end products (AGEs) in the development of diabetic vascular complications and cardiovascular diseases (CVDs). We have shown that high-molecular-weight AGEs (HMW-AGEs), present in our Western diet, impair cardiac function. Whether HMW-AGEs affect vascular function remains unknown. In this study, we aimed to investigate the impact of chronic HMW-AGEs exposure on vascular function and structure. Adult male Sprague Dawley rats were daily injected with HMW-AGEs or control solution for 6 weeks. HMW-AGEs animals showed intracardiac pressure overload, characterized by increased systolic and mean pressures. The contraction response to PE was increased in aortic rings from the HMW-AGEs group. Relaxation in response to ACh, but not SNP, was impaired by HMW-AGEs. This was associated with reduced plasma cyclic GMP levels. SOD restored ACh-induced relaxation of HMW-AGEs animals to control levels, accompanied by a reduced half-maximal effective dose (EC50). Finally, collagen deposition and intima-media thickness of the aortic vessel wall were increased with HMW-AGEs. Our data demonstrate that chronic HMW-AGEs exposure causes adverse vascular remodelling. This is characterised by disturbed vasomotor function due to increased oxidative stress and structural changes in the aorta, suggesting an important contribution of HMW-AGEs in the development of CVDs
Advanced Glycation End Products Impair Cardiac Atrial Appendage Stem Cells Properties
No full textBackground: During myocardial infarction (MI), billions of cardiomyocytes are lost. The optimal therapy should effectively replace damaged cardiomyocytes, possibly with stem cells able to engraft and differentiate into adult functional cardiomyocytes. As such, cardiac atrial appendage stem cells (CASCs) are suitable candidates. However, the presence of elevated levels of advanced glycation end products (AGEs) in cardiac regions where CASCs are transplanted may affect their regenerative potential. In this study, we examine whether and how AGEs alter CASCs properties in vitro. Methods and Results: CASCs in culture were exposed to ranging AGEs concentrations (50 µg/mL to 400 µg/mL). CASCs survival, proliferation, and migration capacity were significantly decreased after 72 h of AGEs exposure. Apoptosis significantly increased with rising AGEs concentration. The harmful effects of these AGEs were partially blunted by pre-incubation with a receptor for AGEs (RAGE) inhibitor (25 µM FPS-ZM1), indicating the involvement of RAGE in the observed negative effects. Conclusion: AGEs have a time- and concentration-dependent negative effect on CASCs survival, proliferation, migration, and apoptosis in vitro, partially mediated through RAGE activation. Whether anti-AGEs therapies are an effective treatment in the setting of stem cell therapy after MI warrants further examination
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