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 ...

Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model

Atherosclerosis is a proliferative fibro-inflammatory disease developing in the arterial wall, inducing a deficient blood flow or a lack of blood flow. ...

RWTH Aachen University, Germany

RWTH Aachen University

Synthesis and biological activity investigation of complex compounds of Cu(II) are challenging issues because of the metal is not a xenobiotic one and the activity of ligands could be modulated by complexation. Complex combinations of Cu(II) and Pd(II) with thiosemicarbazone derivatives of 2-hydroxy-8-R-tricyclo[7.3.1.0.(2,7)]tridecane-13-one (where R=C(3)H(7), C(4)H(3)O) were synthesized. The characterization of the ligands and the newly formed compounds was done by (1)H NMR, (13)C NMR, UV-vis, IR, ESR spectroscopy, elemental analysis, molar electric conductibility and thermal studies. Experiments performed to identify the structures proved that the ligands coordinate to metal ions in different ways - neutral bidentate or mononegative bidentate. Also, if copper(II) acetate, copper(II) nitrate, copper(II) chloride and copper(II) thiocyanate were used, the ligands coordinated in a mononegative bidentate fashion. If copper(II) sulfate was used, the ligands coordinated in a neutral bidentate fashion. The biological activity for the copper(II) synthesized compounds was assessed in terms of antibacterial or antiproliferative activity. The antibacterial activity of the complexes against Staphylococcus aureus var. Oxford 6538, Escherichia coli ATCC 10536, Klebsielle pneumoniae ATCC 100131 and Candida albicans ATCC 10231 strains was studied and compared with that of free ligands. The effect of complex compounds on the proliferation of HeLa cells was tested. For all tested complexes an antiproliferative activity was noted at concentrations higher than 1 microM, but lower than 10 microM. Therefore, complex compounds of copper(II) were synthesized, structurally characterized and tested for biological activity, proving both antibacterial and antiproliferative activity.

Synthesis, characterization antibacterial and antiproliferative activity of novel Cu(II) and Pd(II) complexes with 2-hydroxy-8-R-tricyclo[7.3.1.0.(2,7)]tridecane-13-one thiosemicarbazone.

A nonagonist monocyte chemotactic protein-1 (MCP-1/CCL2) mutant (PA508) with increased affinity for glycosaminoglycans and thus competing with CCL2 was evaluated as a candidate for preventing neointima formation or myocardial ischemia/reperfusion injury.

A new monocyte chemotactic protein-1/chemokine CC motif ligand-2 competitor limiting neointima formation and myocardial ischemia/reperfusion injury in mice.

Un mutant de prot&eacute;ine chimiotactique-1 (MCP-1/CCL2) de monocyte nonagonist (PA508) avec une affinit&eacute; accrue pour les glycosaminoglycanes et ainsi concurrencer CCL2 a &eacute;t&eacute; &eacute;valu&eacute; en tant que candidat pour emp&ecirc;cher la formation n&eacute;o-intimale ou isch&eacute;mie/reperfusion myocardique.

Un nouveau monocyte chimiotactique prot&eacute;ine-1/chemokine CC motif ligand-2 concurrent limitant la formation n&eacute;o-intimale et isch&eacute;mie myocardique/reperfusion chez la souris.

Un mutante di proteina chemiotattica-1 (MCP-1/CCL2) di monociti (PA508) nonagonist con maggiore affinit&agrave; per i glicosaminoglicani e quindi competere con CCL2 &egrave; stato valutato come un candidato per prevenire la formazione di neointima o lesioni del miocardio ischemia/reperfusion.

Un nuovo monocita chemiotattico protein-1/chemochine CC motivo ligando-2 concorrente limitando la formazione di neointima e lesioni del miocardio ischemia/reperfusion nei topi.

Malgr&eacute; des progr&egrave;s consid&eacute;rables au cours des derni&egrave;res d&eacute;cennies, infarctus aigu du myocarde continue &agrave; &ecirc;tre la principale cause de morbidit&eacute; et de mortalit&eacute; dans le monde. Les th&eacute;rapies actuelles comprennent des interventions de cause d&eacute;pendant uniquement, qui ne sont pas en mesure de r&eacute;duire de n&eacute;crose myocardique et optimiser la r&eacute;paration cardiaque apr&egrave;s infarctus du myocarde. Cet examen met en &eacute;vidence les processus cellulaires et mol&eacute;culaires apr&egrave;s l&eacute;sion myocardique et met l&#39;accent sur les chimiokines, les modulateurs principales des manifestations inflammatoires et r&eacute;paratrices, comme les cibles de m&eacute;dicaments plus pr&eacute;cieuses.

R&eacute;paration apr&egrave;s infarctus du myocarde, entre r&ecirc;ve et r&eacute;alit&eacute; : le r&ocirc;le des chimiokines.

Nonostante i notevoli progressi compiuti negli ultimi decenni, infarto miocardico acuto continua a rimanere la principale causa di morbidit&agrave; e mortalit&agrave; in tutto il mondo. Le terapie attuali comprendono interventi solo causa-dipendente, che non sono in grado di ridurre la necrosi del miocardio e ottimizzare la riparazione cardiaca dopo un infarto. Questa recensione mette in evidenza i processi cellulari e molecolari dopo la ferita del miocardio e si concentra su chemiochine, i modulatori principali degli eventi infiammatori e riparatrice, come gli obiettivi pi&ugrave; importanti di droga.

Riparazione dopo infarto miocardico, tra fantasia e realt&agrave;: il ruolo delle chemochine.

Despite considerable progress over the last decades, acute myocardial infarction continues to remain the major cause of morbidity and mortality worldwide. The present therapies include only cause-dependent interventions, which are not able to reduce myocardial necrosis and optimize cardiac repair following infarction. This review highlights the cellular and molecular processes after myocardial injury and focuses on chemokines, the main modulators of the inflammatory and reparatory events, as the most valuable drug targets.

Repair after myocardial infarction, between fantasy and reality: the role of chemokines.

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.

The purposes of this study were the development and preclinical evaluation of clinically translatable E-selectin-specific ultrasound contrast agents based on a peptide ligand with the recognition sequence IELLQAR.

Ultrasound molecular imaging of E-selectin in tumor vessels using poly n-butyl cyanoacrylate microbubbles covalently coupled to a short targeting peptide.

The ability to image incipient atherosclerosis is based on the early events taking place at the endothelial level. We hypothesized that the expression of intercellular adhesion molecule-1 even in vessels with high flow rates can be imaged at the molecular level using 2 complementary imaging techniques: 2-photon laser scanning microscopy and contrast-enhanced ultrasound.

Rhodamine-loaded intercellular adhesion molecule-1-targeted microbubbles for dual-modality imaging under controlled shear stresses.

Microbubbles (MB) are routinely used as contrast agents for functional and molecular ultrasound (US) imaging. For molecular US imaging, MB are functionalized with antibodies or peptides, in order to visualize receptor expression by angiogenic or inflamed endothelium. In general, initial in vitro binding studies with targeted MB are performed using phase contrast microscopy. Difficulties in the identification of MB in standard phase contrast microscopy, however, generally result in high variability, high observer dependency, and low reproducibility. To overcome these shortcomings, we here describe a simple post-loading strategy for labeling polymer-based MB with fluorophores, and we show that the use of rhodamine-loaded MB in combination with fluorescence microscopy substantially reduces the variability and the observer dependency of in vitro binding studies. In addition, we demonstrate that rhodamine-loaded MB can also be used for in vivo and ex vivo experimental setups, e.g., for analyzing MB binding to inflamed carotids using two-photon laser scanning microscopy, and for validating the binding of VEGFR2-targeted MB to tumor endothelium. These findings demonstrate that fluorescently labeled MB substantially facilitate translational molecular US studies, and they suggest that a similar synthetic strategy can be exploited for preparing drug-loaded MB, to enable image-guided, targeted, and triggered drug delivery to tumors and to sites of inflammation.

Fluorescently labeled microbubbles for facilitating translational molecular ultrasound studies.

Cardiovascular interventions induce damage to the vessel wall making antithrombotic therapy inevitable until complete endothelial recovery. Without a method to accurately determine the endothelial status, many patients undergo prolonged anticoagulation therapy, denying them any invasive medical procedures, such as surgical operations and dental interventions. Therefore, we aim to introduce molecular ultrasound imaging of the vascular cell adhesion molecule (VCAM)-1 using targeted poly-n-butylcyanoacrylate microbubbles (MBVCAM-1) as an easy accessible method to monitor accurately the reendothelialization of vessels.

Adelina Curaj

Institute for Molecular Cardiovascular Research

RWTH Aachen University, Germany

Minimal Invasive Surgical Procedure of Inducing Myocardial Infarction in Mice

Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model

Adelina Curaj

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Institute for Molecular Cardiovascular Research

RWTH Aachen University, Germany

Minimal Invasive Surgical Procedure of Inducing Myocardial Infarction in Mice

Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model

Institute for Molecular Cardiovascular Research