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Petz, Anne;
Grandoch, Maria;
Gorski, Daniel J.;
Abrams, Marcel;
Piroth, Marco;
Schneckmann, Rebekka;
Homann, Susanne;
Müller, Julia;
Hartwig, Sonja;
Lehr, Stefan;
Yamaguchi, Yu;
Wight, Thomas N.;
Gorressen, Simone;
Ding, Zhaoping;
Kötter, Sebastian;
Krüger, Martina;
Heinen, Andre;
Kelm, Malte;
Gödecke, Axel;
Flögel, Ulrich;
Fischer, Jens W.
Cardiac Hyaluronan Synthesis Is Critically Involved in the Cardiac Macrophage Response and Promotes Healing After Ischemia Reperfusion Injury
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- Medientyp: E-Artikel
- Titel: Cardiac Hyaluronan Synthesis Is Critically Involved in the Cardiac Macrophage Response and Promotes Healing After Ischemia Reperfusion Injury
- Beteiligte: Petz, Anne; Grandoch, Maria; Gorski, Daniel J.; Abrams, Marcel; Piroth, Marco; Schneckmann, Rebekka; Homann, Susanne; Müller, Julia; Hartwig, Sonja; Lehr, Stefan; Yamaguchi, Yu; Wight, Thomas N.; Gorressen, Simone; Ding, Zhaoping; Kötter, Sebastian; Krüger, Martina; Heinen, Andre; Kelm, Malte; Gödecke, Axel; Flögel, Ulrich; Fischer, Jens W.
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Erschienen:
Ovid Technologies (Wolters Kluwer Health), 2019
- Erschienen in: Circulation Research
- Sprache: Englisch
- DOI: 10.1161/circresaha.118.313285
- ISSN: 0009-7330; 1524-4571
- Entstehung:
- Anmerkungen:
- Beschreibung: <jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p>Immediate changes in the ECM (extracellular matrix) microenvironment occur after myocardial ischemia and reperfusion (I/R) injury.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>Aim of this study was to unravel the role of the early hyaluronan (HA)-rich ECM after I/R.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p> Genetic deletion of <jats:italic>Has2</jats:italic> and <jats:italic>Has1</jats:italic> was used in a murine model of cardiac I/R. Chemical exchange saturation transfer imaging was adapted to image cardiac ECM post-I/R. Of note, the cardiac chemical exchange saturation transfer signal was severely suppressed by <jats:italic>Has2</jats:italic> deletion and pharmacological inhibition of HA synthesis 24 hours after I/R. <jats:italic>Has2</jats:italic> KO ( <jats:italic>Has2</jats:italic> deficient) mice showed impaired hemodynamic function suggesting a protective role for endogenous HA synthesis. In contrast to <jats:italic>Has2</jats:italic> deficiency, <jats:italic>Has1</jats:italic> -deficient mice developed no specific phenotype compared with control post-I/R. Importantly, in <jats:italic>Has2</jats:italic> KO mice, cardiac macrophages were diminished after I/R as detected by <jats:sup>19</jats:sup> F MRI (magnetic resonance imaging) of perfluorcarbon-labeled immune cells, Mac-2/Galectin-3 immunostaining, and FACS (fluorescence-activated cell sorting) analysis (CD45 <jats:sup>+</jats:sup> CD11b <jats:sup>+</jats:sup> Ly6G <jats:sup>−</jats:sup> CD64 <jats:sup>+</jats:sup> F4/80 <jats:sup>+</jats:sup> cells). In contrast to macrophages, cardiac Ly6C <jats:sup>high</jats:sup> and Ly6C <jats:sup>low</jats:sup> monocytes were unaffected post-I/R compared with control mice. Mechanistically, inhibition of HA synthesis led to increased macrophage apoptosis in vivo and in vitro. In addition, α-SMA (α-smooth muscle actin)–positive cells were reduced in the infarcted myocardium and in the border zone. In vitro, the myofibroblast response as measured by <jats:italic>Acta2</jats:italic> mRNA expression was reduced by inhibition of HA synthesis and of CD44 signaling. Furthermore, <jats:italic>Has2</jats:italic> KO fibroblasts were less able to contract collagen gels in vitro. The effects of HA/CD44 on fibroblasts and macrophages post-I/R might also affect intercellular cross talk because cardiac fibroblasts were activated by monocyte/macrophages and, in turn, protected macrophages from apoptosis. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p>Increased HA synthesis contributes to postinfarct healing by supporting macrophage survival and by promoting the myofibroblast response. Additionally, imaging of cardiac HA by chemical exchange saturation transfer post-I/R might have translational value.</jats:p> </jats:sec>
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