miR155 Deficiency Reduces Myofibroblast Density but Fails to Improve Cardiac Function after Myocardial Infarction in Dyslipidemic Mouse Model

Myocardial infarction remains the most common cause of heart failure with adverse remodeling. MicroRNA (miR)155 is upregulated following myocardial infarction and represents a relevant regulatory factor for cardiac remodeling by engagement in cardiac inflammation, fibrosis and cardiomyocyte hypertrophy. Here, we investigated the role of miR155 in cardiac remodeling and dysfunction following myocardial infarction in a dyslipidemic mouse model. Myocardial infarction was induced in dyslipidemic apolipoprotein E-deficient (ApoE−/−) mice with and without additional miR155 knockout by ligation of the LAD. Four weeks later, echocardiography was performed to assess left ventricular (LV) dimensions and function, and mice were subsequently sacrificed for histological analysis. Echocardiography revealed no difference in LV ejection fractions, LV mass and LV volumes between ApoE−/− and ApoE−/−/miR155−/− mice. Histology confirmed comparable infarction size and unaltered neoangiogenesis in the myocardial scar. Notably, myofibroblast density was significantly decreased in ApoE−/−/miR155−/− mice compared to the control, but no difference was observed for total collagen deposition. Our findings reveal that genetic depletion of miR155 in a dyslipidemic mouse model of myocardial infarction does not reduce infarction size and consecutive heart failure but does decrease myofibroblast density in the post-ischemic scar

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

Background-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. Methods and Results-Mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C5aRA and anti-C5aR-blocking monoclonal antibody or vehicle control. Compared with controls, neointima formation was significantly reduced in mice receiving C5aRA or anti-C5aR-blocking monoclonal antibody for 1 week but not for 3 weeks, attributable to an increased content of vascular smooth muscle cells, whereas a marked decrease in monocyte and neutrophil content was associated with reduced vascular cell adhesion molecule-1. As assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry, C5aR was expressed in lesional and cultured vascular smooth muscle cells, upregulated by injury or tumor necrosis factor-alpha, and reduced by C5aRA. Plasma levels and neointimal plasminogen activator inhibitor-1 peaked 1 week after injury and were downregulated in C5aRA-treated mice. In vitro, C5a induced plasminogen activator inhibitor-1 expression in endothelial cells and vascular smooth muscle cells in a C5aRA-dependent manner, possibly accounting for higher vascular smooth muscle cell immigration. Conclusions-One-week treatment with C5aRA or anti-C5aR-blocking monoclonal antibody limited neointimal hyperplasia and inflammatory cell content and was associated with reduced vascular cell adhesion molecule-1 expression. However, treatment for 3 weeks failed to reduce but rather stabilized plaques, likely by reducing vascular plasminogen activator inhibitor-1 and increasing vascular smooth muscle cell migration. (Circulation. 2010;122:1026-1036.

Differential Role for Activating Fc gamma RIII in Neointima Formation After Arterial Injury and Diet-Induced Chronic Atherosclerosis inApolipoprotein E-Deficient Mice

Atherogenesis and arterial remodeling following mechanical injury are driven by inflammation and mononuclear cell infiltration. The binding of immune complexes (ICs) to immunoglobulin (Ig)-Fc gamma receptors (Fc gamma Rs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of Fc gamma RIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of Fc gamma RIII in diet-induced chronic atherosclerosis.Fc gamma rIII(-/-)/Apoe(-/-)and controlApoe(-/-)mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD).Fc gamma rIIIdeficiency mitigated neointimal plaque formation and lesional macrophage accumulation, and enhanced neointimal vascular smooth muscle cell (VSMC) numbers. This went along with a reduced expression of tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1/CCL2), and vascular cell adhesion molecule-1 (VCAM-1) in the neointimal lesions. Interestingly, in a chronic model of diet-induced atherosclerosis, we unraveled a dichotomic role of Fc gamma RIII in an early versus advanced stage of the disease. WhileFc gamma rIIIdeficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end,Fc gamma rIIIdeficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect ofFc gamma rIIIdeficiency in late-stage atherosclerosis revealed increased serum levels of anti-oxidized-LDL immunoglobulins IgG2c and IgG2b. This was paralleled by enhanced lesional accumulation of IgGs without affecting levels of complement-activated products C5a or C5ar1, Fc gamma RII, and Fc gamma RIV. Moreover,Fc gamma rIII-deficient macrophages expressed moreFc gamma rII,Tnf-alpha, andIl-1 beta mRNA when exposed to IgG1 or oxLDL-IgG1 ICsin vitro, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activatingFc gamma RIIIlimits neointima formation after arterial injury in atherosclerosis-prone mice as well as early stage chronic atherosclerosis, but augments late-stage atherosclerosis suggesting a dual role of Fc gamma RIII in atherogenic inflammation

Mastoidrekonstruktion mit einem Titangitter

Einleitung: Bei der Cholesteatomsanierung hat sich die am Entstehungsweg orientierende Operationsmethode bewährt. Dabei wird das Cholesteatom vom Entstehungsort unter Abfräsen der hinteren Gehörgangswand und des lateralen Mastoids freigelegt. Zur Wiederherstellung ursprünglicher Verhältnisse ist die Rekonstruktion der hinteren Gehörgangswand angezeigt. Knorpel allein erweist sich häufig als zu wenig resistent. Alle bisherigen Methoden der Rekonstruktion haben sich rein auf die Hinterwand beschränkt. Das hier vorgestellte Verfahren zielt auf eine gesamte Rekonstruktion des Mastoids einschließlich septaler Strukturen ab. Methode: 10 Patienten, bei denen eine Mastoidrekonstruktion mit Titan-Gitter vorgenommen wurde, konnten ausgewertet werden. Das Gitter wurde derart gestaltet, dass nicht nur die Gehörgangshinterwand sondern auch das Trabekelsystem des Mastoids nachgebildet wurde. Die Bedeckung erfolgte mit Knorpel. Ergebnisse: Bei allen Patienten kam es zu einer regelhaften Abheilung des Gehörgangs. Der Knorpel heilte problemlos ein mit vollständiger Epithelisierung, freiliegendes Implantatmaterial wurde in keinem Fall beobachtet. Die durchschnittliche Nachbeobachtungszeit beträgt derzeit 17,75 Monate (minimal 9 Monate, maximal 26 Monate).Schlussfolgerung: Die Methode der Mastoidrekonstruktion scheint gegenüber der reinen Rekonstruktion der Hinterwand, die meist mit Verschraubungen vorgenommen wurden, deutliche Vorteile zu haben. Eine bessere Bedeckung mit Knorpel und die abstützende Funktion des Trabekelwerkes scheint hier wesentlich zu sein, wobei die bekannte Mittelohrkompatibiliät von Titan sicher mitentscheidend ist