Cardiac Hyaluronan Synthesis Is Critically Involved in the Cardiac Macrophage Response and Promotes Healing After Ischemia Reperfusion Injury

作者：Anne Petz, Maria Grandoch, Daniel J. Gorski, Marcel Abrams, Marco Piroth, Rebekka Schneckmann, Susanne Homann, Julia Müller, Sonja Hartwig, Stefan Lehr, Yu Yamaguchi, Thomas N. Wight, Simone Gorreßen, Zhaoping Ding, Sebastian Kötter, Martina Krüger, André Heinen, Malte Kelm, Axel Gödecke, Ulrich Flögel, Jens W. Fischer · 发表于：Circulation Research · 年份：2019 · DOI：10.1161/circresaha.118.313285 · 被引用次数：76 · 研究领域：Proteoglycans and glycosaminoglycans research、Cardiac Fibrosis and Remodeling、Tissue Engineering and Regenerative Medicine

Rationale: Immediate changes in the ECM (extracellular matrix) microenvironment occur after myocardial ischemia and reperfusion (I/R) injury. Objective: Aim of this study was to unravel the role of the early hyaluronan (HA)-rich ECM after I/R. Methods and Results: Genetic deletion of Has2 and Has1 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 Has2 deletion and pharmacological inhibition of HA synthesis 24 hours after I/R. Has2 KO ( Has2 deficient) mice showed impaired hemodynamic function suggesting a protective role for endogenous HA synthesis. In contrast to Has2 deficiency, Has1 -deficient mice developed no specific phenotype compared with control post-I/R. Importantly, in Has2 KO mice, cardiac macrophages were diminished after I/R as detected by 19 F MRI (magnetic resonance imaging) of perfluorcarbon-labeled immune cells, Mac-2/Galectin-3 immunostaining, and FACS (fluorescence-activated cell sorting) analysis (CD45 + CD11b + Ly6G − CD64 + F4/80 + cells). In contrast to macrophages, cardiac Ly6C high and Ly6C low 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....