a-murine-model-stent-implantation-carotid-artery-for-study

A Murine Model of Stent Implantation in the Carotid Artery for the Study of Restenosis

Despite  the considerable progress made in the stent development in the last decades,  cardiovascular diseases remain the main cause of death in western ...

minimal-invasive-surgical-procedure-inducing-myocardial-infarction

Minimal Invasive Surgical Procedure of Inducing Myocardial Infarction in Mice

Myocardial infarction still remains the main cause of death in western countries, despite considerable progress in the stent development area in the last ...

implantation-human-sized-coronary-stents-into-rat-abdominal-aorta

Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of ...

RWTH Aachen University

RWTH Aachen University, Germany

University Hospital RWTH Aachen

Receptor binding of complement C5a leads to proinflammatory activation of many cell types, but the role of receptor-mediated action during arterial remodeling after injury has not been studied. In the present study, we examined the contribution of the C5a receptor (C5aR) to neointima formation in apolipoprotein E-deficient mice employing a C5aR antagonist (C5aRA) and a C5aR-blocking monoclonal antibody.

C5a receptor targeting in neointima formation after arterial injury in atherosclerosis-prone mice.

Liaison aux r&eacute;cepteurs du compl&eacute;ment que C5a conduit &agrave; l&#39;activation de proinflammatory de nombreux types cellulaires, mais le r&ocirc;le d&#39;action m&eacute;di&eacute;e par les r&eacute;cepteurs au cours de remodelage art&eacute;riel apr&egrave;s que blessure n&#39;a pas &eacute;t&eacute; &eacute;tudi&eacute;e. Dans la pr&eacute;sente &eacute;tude, nous avons examin&eacute; la contribution du r&eacute;cepteur C5a (C5aR) pour formation n&eacute;o-intimale en apolipoprot&eacute;ine E-deficient mice employant un antagoniste C5aR (C5aRA) et un anticorps monoclonal bloquant C5aR.

C5a ciblant les r&eacute;cepteurs en formation n&eacute;o-intimale apr&egrave;s une l&eacute;sion art&eacute;rielle chez les souris sujettes &agrave; l&#39;ath&eacute;roscl&eacute;rose.

Associazione del recettore del complemento che C5a conduce a proinfiammatorio attivazione di molti tipi di cellule, ma il ruolo dell&#39;azione mediata dal recettore durante il rimodellamento arterioso dopo l&#39;infortunio non &egrave; stato studiato. Nel presente studio, abbiamo esaminato il contributo del recettore C5a (C5aR) alla formazione di neointima nei topi apolipoproteina E-deficienti che impiegano un antagonista di C5aR (C5aRA) e un anticorpo monoclonale C5aR di blocco.

C5a recettore targeting in formazione di neointima dopo lesioni arteriose nei topi l&#39;aterosclerosi-inclini.

Percutaneous transluminal angioplasty with stent implantation is used to dilate arteries narrowed by atherosclerotic plaques and to revascularize coronary arteries occluded by atherothrombosis in myocardial infarction. Commonly applied drug-eluting stents release antiproliferative or anti-inflammatory agents to reduce the incidence of in-stent stenosis. However, these stents may still lead to in-stent stenosis; they also show increased rates of late stent thrombosis, an obstacle to optimal revascularization possibly related to endothelial recovery. Here, we examined the contribution of neutrophils and neutrophilic granule proteins to arterial healing after injury. We found that neutrophil-borne cathelicidin (mouse CRAMP, human LL-37) promoted reendothelization and thereby limited neointima formation after stent implantation. We then translated these findings to an animal model using a neutrophil-instructing, biofunctionalized, miniaturized Nitinol stent coated with LL-37. This stent reduced in-stent stenosis in a mouse model of atherosclerosis, suggesting that LL-37 may promote vascular healing after interventional therapy.

Neutrophil-derived cathelicidin protects from neointimal hyperplasia.

L&#39;angioplastie transluminale percutan&eacute;e avec implantation de stents sert &agrave; dilater les art&egrave;res r&eacute;tr&eacute;cies par des plaques d&#39;ath&eacute;roscl&eacute;rose et &agrave; recanalisent des art&egrave;res coronaires occlus par ath&eacute;rothrombose dans l&#39;infarctus du myocarde. Couramment appliqu&eacute;es des stents &agrave; &eacute;lution m&eacute;dicamenteuse lib&eacute;rer des agents antiprolif&eacute;ratifs ou anti-inflammatoire pour r&eacute;duire l&#39;incidence de la st&eacute;nose intrastent. Cependant, ces stents peut induire encore intrastent st&eacute;nose ; ils montrent &eacute;galement une augmentation des taux de retard thrombose de stent, un obstacle &agrave; la revascularisation optimale &eacute;ventuellement li&eacute;es &agrave; la r&eacute;cup&eacute;ration endoth&eacute;liale. Ici, nous avons examin&eacute; la contribution des neutrophiles et des prot&eacute;ines de neutrophiles granule &agrave; art&eacute;riel de gu&eacute;rison apr&egrave;s une blessure. Nous avons trouv&eacute; que cath&eacute;licidine transmises par les neutrophiles (souris CRAMPE, humain LL-37) promu reendothelization et formation n&eacute;ointima ainsi limit&eacute;e apr&egrave;s implantation de stents. Nous avons ensuite traduit ces r&eacute;sultats d&#39;un mod&egrave;le animal en utilisant un neutrophile-instruire, la biofunctionalized, miniaturis&eacute; stent Nitinol recouvert de LL-37. Cette endoproth&egrave;se r&eacute;duit intrastent st&eacute;nose dans un mod&egrave;le murin de l&#39;ath&eacute;roscl&eacute;rose, ce qui sugg&egrave;re que LL-37 peut favoriser la cicatrisation vasculaire apr&egrave;s traitement interventionnel.

D&eacute;riv&eacute; de neutrophile cath&eacute;licidine prot&egrave;ge contre l&#39;hyperplasie n&eacute;ointimale.

Angioplastica transluminale percutanea con impianto di stent viene utilizzato per dilatare le arterie ridotte da placche aterosclerotiche e revascularize arterie coronarie occluse da ATEROTROMBOSI nell&#39;infarto miocardico. Comunemente applicato stent medicati rilasciare agenti antiproliferativi o anti-infiammatori per ridurre l&#39;incidenza di stenosi in-stent. Tuttavia, questi stent pu&ograve; ancora portare a stenosi di stent; essi mostrano anche tassi di aumentati del tardo trombosi dello stent, un ostacolo all&#39;ottima rivascolarizzazione possibilmente correlate al ripristino endoteliale. Qui, abbiamo esaminato il contributo di neutrofili e proteine neutrofila granulo alla guarigione arteriosa dopo l&#39;infortunio. Abbiamo trovato che cathelicidin neutrofili-borne (mouse CRAMPO, LL umano-37) promosso reendothelization e formazione di neointima quindi limitato dopo l&#39;impianto dello stent. Poi abbiamo tradotto questi risultati in un modello animale utilizzando un neutrofili-istruire, biofunctionalized, miniaturizzato stent in Nitinol rivestiti con LL-37. Questo stent ridotto in-stent stenosi in un modello murino di aterosclerosi, suggerendo che LL-37 pu&ograve; favorire la guarigione vascolare dopo terapia interventistica.

Neutrofili derivata cathelicidin protegge da iperplasia neointimale.

This study aimed to analyze the role of endothelial progenitor cell (EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor (MIF)/chemokine receptor axis. Primary murine and murine embryonic EPCs (eEPCs) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis, focusing on the influence of hypoxic versus normoxic stimulation. Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These factors stimulated the transmigration activity and adhesive capacity of EPCs, with MIF and VEGF exhibiting the strongest effects under hypoxia. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs enhanced tube formation, with MIF and VEGF exhibiting again the strongest effect following hypoxia. Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF. Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12, whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell (SMC) phenotype, indicating an angiogenic and differentiation capacity in vivo. Surprisingly, CXCL12, a chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. We have identified a role for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. By discerning the contributions of key angiogenic chemokines and EPCs, these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors, EPCs, and the angiogenic target tissue.

Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis.

Cette &eacute;tude visait &agrave; analyser le r&ocirc;le des cellules endoth&eacute;liales prog&eacute;nitrices (CBE)-d&eacute;riv&eacute; de facteurs angiog&eacute;niques et chimiokines dans le processus multipas conduite angiogen&egrave;se en mettant l&#39;accent sur le facteur inhibiteur de la migration de macrophage r&eacute;cemment d&eacute;couverts (MIF) / axe de r&eacute;cepteur de chimiokine. Primaires EPCs embryonnaires murins et murins (eEPCs) ont &eacute;t&eacute; analys&eacute;s pour l&#39;expression d&#39;angiog&eacute;niques/chimiokines et composantes de l&#39;axe de r&eacute;cepteur de chimiokine MIF/CXC, mettant l&#39;accent sur l&#39;influence de l&#39;hypoxie versus stimulation normoxique. Hypoxie induite par une stimulation de l&#39;expression de CXCR2 et CXCR4 mais pas CD74 sur EPCs et d&eacute;clenche la s&eacute;cr&eacute;tion de CXCL12, CXCL1, MIF et facteur de croissance endoth&eacute;lial vasculaire (VEGF). Ces facteurs ont stimul&eacute; la capacit&eacute; de l&#39;activit&eacute; et adh&eacute;sif de transmigration du CPE, avec MIF et VEGF pr&eacute;sentant les plus forts effets en vertu de l&#39;hypoxie. MIF-, VEGF - CXCL12-, formation et EPCs stimul&eacute;e par CXCL1 tube am&eacute;lior&eacute;e, avec la MIF et VEGF pr&eacute;sentant &agrave; nouveau le plus fort effet suite &agrave; l&#39;hypoxie. Formation du tube apr&egrave;s l&#39;implantation in vivo utilisant des bouchons de Matrigel charg&eacute;s en facteur angiog&eacute;nique est promue seulement de VEGF. Coloading de bougies d&#39;eEPCs conduit &agrave; tube meilleure formation uniquement par CXCL12, tandis que MIF a &eacute;t&eacute; le seul facteur qui induit la diff&eacute;renciation vers un ph&eacute;notype de cellule (SMC) endoth&eacute;liale et des muscles lisses, ce qui indique une capacit&eacute; angiog&eacute;nique et diff&eacute;renciation in vivo. &Eacute;tonnamment, CXCL12, un facteur chimiotactique pour les cellules prog&eacute;nitrices musculaires lisses, inhibe la diff&eacute;renciation SMC. Nous avons identifi&eacute; un r&ocirc;le pour CBE-d&eacute;riv&eacute; on MIF, VEGF et traitent les r&eacute;cepteurs de la MIF dans le recrutement de CBE apr&egrave;s l&#39;hypoxie, la diff&eacute;renciation de l&#39;EPC et tube ult&eacute;rieur et la formation de vaisseaux, tandis que CXCL12, un m&eacute;diateur du recrutement pr&eacute;coce de CBE, ne contribue pas &agrave; la retouche. De discerner les contributions des chimiokines angiog&eacute;niques cl&eacute;s et EPCs, ces r&eacute;sultats offrent un aper&ccedil;u pr&eacute;cieux m&eacute;caniste dans des mod&egrave;les murins de l&#39;angiogen&egrave;se et aident &agrave; d&eacute;finir les interactions complexes entre facteurs de cargaison angiog&eacute;nique d&eacute;riv&eacute; de CBE, EPCs et le tissu de cible angiog&eacute;nique.

R&ocirc;les diff&eacute;rentiels des chimiokines angiog&eacute;nique dans l&#39;angiogen&egrave;se d&#39;induite sur les cellules endoth&eacute;liales prog&eacute;nitrices.

Questo studio finalizzato ad analizzare il ruolo delle cellule progenitrici endoteliali (EPC)-derivato fattori angiogenetici e chemochine nel processo multifasico guida angiogenesi con un focus sul fattore inibitorio di migrazione dei macrofagi recentemente scoperto (MIF) / asse di chemokine receptor. Primaria murino e murino EPCs embrionali (eEPCs) sono stati analizzati per l&#39;espressione di angiogenic/chemiochine e componenti dell&#39;asse MIF/CXC chemokine receptor, concentrandosi sull&#39;influenza di versus normossiche stimolazione ipossica. Ipossia indotta una sovraregolazione di CXCR2 e CXCR4 ma non CD74 su EPC e innescato la secrezione di CXCL12, CXCL1, MIF e fattore di crescita endoteliale vascolare (VEGF). Questi fattori ha stimolato la capacit&agrave; di attivit&agrave; e adesivo trasmigrazione delle EPCs, MIF e VEGF esporre gli effetti pi&ugrave; forti sotto l&#39;ipossia. MIF-, VEGF - CXCL12-, formazione e stimolato CXCL1 EPCs enhanced tubo, con MIF e VEGF esibendo ancora una volta l&#39;effetto pi&ugrave; forte seguito di ipossia. Formazione del tubo seguente l&#39;impianto in vivo utilizzando angiogenic factor-caricato Matrigel spine solo fu promosso da VEGF. Coloading di spine con eEPCs portato a tubo avanzato formazione solo CXCL12, considerando che la MIF &egrave; stato l&#39;unico fattore che induce la differenziazione verso un fenotipo (SMC) di cellule endotelio e muscolari lisce, che indica una capacit&agrave; angiogenica e differenziazione in vivo. Sorprendentemente, CXCL12, un chemoattractant per muscolo liscio cellule progenitrici, inibito differenziazione SMC. Abbiamo identificato un ruolo per EPC-derivato proangiogenic MIF, VEGF e recettori MIF nel reclutamento di EPC dopo ipossia, EPC differenziazione e successiva tubo e formazione di nave, considerando che CXCL12, un mediatore dell&#39;inizio del reclutamento di EPC, non contribuiscono per il rimodellamento di processo. Di discernere i contributi della chiave angiogenic chemiochine ed EPCs, questi risultati offrono informazioni preziose meccanicistico in modelli murini di angiogenesi e contribuiscono a definire la complessa interazione tra EPC-derivato angiogenic fattori di carico, EPC e il tessuto bersaglio angiogenic.

Differenziali ruoli di angiogenic chemochine nella angiogenesi indotta in cellule progenitrici endoteliali.

BACKGROUND: Chemokines and neutrophils, known as important players in the inflammatory cascade, also contribute to heart tissue recovery and scar formation after myocardial infarction (MI). The objective of this study was to determine the importance of ELR-containing CXC chemokine KC in neutrophil infiltration and neoangiogenesis, in a mouse model of chronic MI. METHODS AND RESULTS: MI was induced in mice divided in four groups: control (untreated), anti-KC "later" (anti-KC antibody injections started 4days after MI and then delivered every 72hours for 3weeks, to inhibit angiogenesis), anti-KC "earlier" (anti-KC antibody injections 1day before and 1day after MI, to block neutrophil infiltration), anti-KC (anti-KC antibody injections 1day before and 1day after MI, and then every 72hours for 3weeks). The efficiency of the anti-KC treatment was determined by the measurement of KC serum concentration and immunofluorescence staining, in each of the four groups. Surprisingly, we did not find any difference in neutrophil infiltration in the infarcted area between untreated and treated animals. Moreover, the heart function, infarct size, and neoangiogenesis were not different between the four groups. As expected, a comparable anti-CXCR2 treatment of mice before and after MI was able to significantly reduce neutrophil infiltration into the infarcted area and angiogenesis, but also to reduce the infarction size after long or "later" treatment. CONCLUSIONS: The major finding of our study is that KC, a potent neutrophil chemoattractant and an established angiogenic factor, failed to interfere in the post-infarction inflammatory response, in wound healing and scar formation after MI. Therefore, these aspects need to be carefully taken into account when devising therapeutic strategies for myocardial infarction and ischemic cardiomyopathy.

CXC chemokine KC fails to induce neutrophil infiltration and neoangiogenesis in a mouse model of myocardial infarction.

Rappel des faits : Chimiokines et neutrophiles, connus comme des acteurs importants dans la cascade inflammatoire, contribuent &eacute;galement &agrave; la formation de r&eacute;cup&eacute;ration et de la cicatrice de tissu cardiaque apr&egrave;s infarctus du myocarde (im). L&#39;objectif de cette &eacute;tude &eacute;tait de d&eacute;terminer l&#39;importance des ERT contenant CXC chimiokines KC en infiltration des neutrophiles et la n&eacute;oangiogen&egrave;se, dans un mod&egrave;le murin de chroniques MI. m&eacute;thodes et r&eacute;sultats: MI a &eacute;t&eacute; induite chez les souris, divis&eacute;s en quatre groupes : contr&ocirc;le (non trait&eacute;s), anti-KC &laquo; plus tard &raquo; (injections d&#39;anticorps anti-KC a commenc&eacute; 4 jours apr&egrave;s MI et ensuite envoy&eacute;es chaque 72hours pour 3 semaines, pour inhiber l&#39;angiogen&egrave;se), anti-KC &laquo; plus t&ocirc;t &raquo; (anticorps anti-KC injections 1 jour avant et 1 jour apr&egrave;s la MIde bloquer l&#39;infiltration des neutrophiles), anti-KC (anticorps anti-KC injections 1 jour avant et 1 jour apr&egrave;s la MI et puis chaque 72hours pour 3 semaines). L&#39;efficacit&eacute; du traitement anti-KC a &eacute;t&eacute; d&eacute;termin&eacute;e en mesurant la concentration s&eacute;rique KC et immunofluorescence souillant, dans chacun des quatre groupes. &Eacute;tonnamment, nous n&#39;avons trouv&eacute; aucune diff&eacute;rence dans l&#39;infiltration de neutrophile dans la zone infarcie entre animaux non trait&eacute;s et trait&eacute;s. En outre, la fonction cardiaque, la taille de l&#39;infarctus et n&eacute;oangiogen&egrave;se n&#39;&eacute;tait pas diff&eacute;rents entre les quatre groupes. Comme pr&eacute;vu, un traitement anti-CXCR2 comparable des souris avant et apr&egrave;s que MI a r&eacute;ussi &agrave; r&eacute;duire de fa&ccedil;on significative l&#39;infiltration de neutrophile dans la zone infarcie et angiogen&egrave;se, mais aussi de r&eacute;duire la taille de l&#39;infarctus du myocarde apr&egrave;s un traitement long ou &laquo; plus tard &raquo;. CONCLUSIONS : Les principales conclusions de notre &eacute;tude sont que KC, un puissant chimioattractant neutrophil et un facteur angiog&eacute;nique &eacute;tablie, n&#39;a pas &agrave; interf&eacute;rer dans la r&eacute;ponse inflammatoire post-infarctus, en formation de gu&eacute;rison et de la cicatrice plaie apr&egrave;s MI. Par cons&eacute;quent, ces aspects doivent &ecirc;tre soigneusement pris en compte lorsqu&#39;ils &eacute;tablissent des strat&eacute;gies th&eacute;rapeutiques pour infarctus du myocarde et une cardiomyopathie isch&eacute;mique.

Chimiokines CXC KC ne parvient pas &agrave; induire l&#39;infiltration de neutrophile et de n&eacute;oangiog&eacute;n&egrave;se dans un mod&egrave;le murin d&#39;infarctus du myocarde.

SFONDO: Chemiochine e neutrofili, noti come giocatori importanti in cascata infiammatoria, anche contribuiscono al tessuto recupero e cicatrice formazione cuore dopo infarto miocardico (MI). L&#39;obiettivo di questo studio era di determinare l&#39;importanza di chemokine CXC contenenti ELR KC nell&#39;infiltrazione dei neutrofili e neoangiogenesis, in un modello murino di cronica assolsero metodi e risultati: MI &egrave; stato indotto nei topi divisi in quattro gruppi: controllo (non trattata), anti-KC &quot;pi&ugrave; tardi&quot; (anticorpo anti-KC iniezioni iniziato 4gg dopo MI e poi consegnato ogni 72hours per 3weeks, per inibire l&#39;angiogenesi), anti-KC &quot;precedenti&quot; (anticorpo anti-KC iniezioni 1 giorno prima e 1 giorno dopo il MIper bloccare l&#39;infiltrazione di neutrofili), anti-KC (anticorpo anti-KC iniezioni 1 giorno prima e 1 giorno dopo MI e poi ogni 72hours per 3weeks). L&#39;efficacia del trattamento anti-KC &egrave; stata determinata con la misurazione della concentrazione sierica KC e immunofluorescenza colorazione, in ciascuno dei quattro gruppi. Sorprendentemente, non abbiamo trovato alcuna differenza nell&#39;infiltrazione dei neutrofili nella zona aneurismatico tra gli animali trattati e non trattati. Inoltre, la funzione del cuore, di infarct e neoangiogenesis non erano diversi tra i quattro gruppi. Come previsto, un anti-CXCR2 paragonabile trattamento dei topi prima e dopo MI &egrave; stato in grado di ridurre significativamente l&#39;infiltrazione dei neutrofili nella zona aneurismatico e l&#39;angiogenesi, ma anche per ridurre la dimensione di infarto dopo trattamento lungo o &quot;pi&ugrave; tardi&quot;. CONCLUSIONI: Il ritrovamento pi&ugrave; importante del nostro studio &egrave; che KC, un chemoattractant potente neutrofilo e un fattore angiogenico stabilito, non &egrave; riuscito ad interferire nella risposta infiammatoria post-infarction, nella formazione di guarigione e cicatrice ferita dopo MI. Pertanto, questi aspetti devono essere attentamente presi in considerazione quando ideare strategie terapeutiche per infarto del miocardio e cardiomiopatia ischemica.

CXC chemokine KC non riesce a indurre l&#39;infiltrazione dei neutrofili e neoangiogenesis in un modello murino di infarto del miocardio.

Here, we aimed to clarify the role of CXC chemokine receptor (CXCR) 2 in macrophage migration-inhibitory factor (MIF)-mediated effects after myocardial ischemia and reperfusion. As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2. In models of myocardial infarction, MIF exerts both proinflammatory effects and protective effects in cardiomyocytes. Similarly, CXCR2 displays opposing effects in resident versus circulating cells.

Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion.

Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage and to act as a proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice.

Role of extracellular RNA in atherosclerotic plaque formation in mice.

The Ikkα kinase, a subunit of the NF-κB-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikkα mutant knock-in on haematopoiesis and atherosclerosis in mice.

Bone marrow-specific knock-in of a non-activatable Ikkα kinase mutant influences haematopoiesis but not atherosclerosis in Apoe-deficient mice.

Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24 hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4 weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies.

Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction.

The Cxcl12/Cxcr4 chemokine ligand/receptor axis mediates the mobilization of smooth muscle cell progenitors, driving injury-induced neointimal hyperplasia. This study aimed to investigate the role of endothelial Cxcr4 in neointima formation.

Deficiency of endothelial CXCR4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in atherosclerosis-prone mice.

Response to letter regarding article "Role of extracellular RNA in atherosclerotic plaque formation in mice".

Cardiovascular disease is the leading cause of death in the western and developing countries. Percutaneous transluminal coronary interventions have become the most prevalent treatment option for coronary artery disease; however, due to serious complications, such as stent thrombosis and in-stent restenosis (ISR), the efficacy and safety of the procedure remain important issues to address. Strategies to overcome these aspects are under extensive investigation. In this review, we summarise relevant milestones during the time to overcome these limitations of coronary stents, such as the development of polymer-free drug-eluting stents (DES) to avoid pro-inflammatory response due to the polymer coating or the developement of stents with cell-directing drugs to, simultaneously, improve re-endothelialisation and inhibit ISR amongst other techniques most recently developed, which have not fully entered the clinical stage. Also the novel concept of fully biodegradable DES featured by the lack of a permanent foreign body promises to be a beneficial and applicable tool to restore a natural vessel with maintained vasomotion and to enable optional subsequent surgical revascularisation.

Progress in interventional cardiology: challenges for the future.

The long-term success of coronary stent implantation is limited by in-stent restenosis (ISR). In spite of a broad variety of animal models available, an ideal high-throughput model of ISR has been lacking. Apolipoprotein E (apoE) deficient rats enable the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. Whereas apoE deficient rats have been proposed as animal model of atherosclerosis, to date it is unknown whether they also develop pronounced ISR. We sought to assess ISR after abdominal aorta stent implantation in apoE deficient rats. A total of 42 rats (16 wildtype, 13 homozygous apoE and 13 heterozygous apoE rats) underwent abdominal aorta stent implantation. After 28 days blood samples were analyzed to characterize lipid profiles. ISR was assessed by histomorphometric means. Homozygous apoE rats exhibited significantly higher total cholesterol and low-density cholesterol levels than wildtype apoE and heterozygous apoE rats. ISR was significantly pronounced in homozygous apoE rats as compared to wildtype apoE (p = <0.0001) and heterozygous apoE rats (p = 0.0102) on western diet. Abdominal aorta stenting of apoE rats is a reliable model to investigate ISR after stent implantation and thus can be used for the evaluation of novel stent concepts. Apolipoprotein E (apoE) deficient rats have been proposed as animal model of atherosclerosis. We investigated the development of restenosis 28 days after stent implantation into the abdominal aorta of wildtype apoE, homozygous apoE and heterozygous apoE rats, respectively. Homozygous apoE rats exhibited significantly higher LDL and significantly lower HDL cholesterol levels compared to wildtype apoE and heterozygous apoE rats. Restenosis after stent implantation was significantly pronounced in western-diet-fed homozygous apoE rats, accompanied by a significantly increased neointimal thickness. Thus, apoE knockout rats exhibit elevated restenosis and might provide a novel tool for testing of innovative stent concepts.

ArticleTotal : 3	Year
Publication title Cited by 11	2013
Publication title Cited by 25	2015
Publication title Cited by 4	2020

Article	Year
C5a receptor targeting in neointima formation after arterial injury in atherosclerosis-prone mice. Circulation\| PubMed ID: 20733098	2010
Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Science translational medicine\| PubMed ID: 21974936	2011
Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis. Basic research in cardiology\| PubMed ID: 23184390	2013
CXC chemokine KC fails to induce neutrophil infiltration and neoangiogenesis in a mouse model of myocardial infarction. Journal of molecular and cellular cardiology\| PubMed ID: 23598282	2013
Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 23868943	2013
Role of extracellular RNA in atherosclerotic plaque formation in mice. Circulation\| PubMed ID: 24201302	2014
Bone marrow-specific knock-in of a non-activatable Ikkα kinase mutant influences haematopoiesis but not atherosclerosis in Apoe-deficient mice. PloS one\| PubMed ID: 24498325	2014
Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction. Journal of cellular and molecular medicine\| PubMed ID: 24512349	2014
Deficiency of endothelial CXCR4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in atherosclerosis-prone mice. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 24723559	2014
Response to letter regarding article "Role of extracellular RNA in atherosclerotic plaque formation in mice". Circulation\| PubMed ID: 25311624	2014
Progress in interventional cardiology: challenges for the future. Thrombosis and haemostasis\| PubMed ID: 25608683	2015
Apolipoprotein E deficient rats generated via zinc-finger nucleases exhibit pronounced in-stent restenosis. Scientific reports\| PubMed ID: 31796798	2019

Sakine Simsekyilmaz

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