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

Rationale: Immediate changes in the extracellular matrix (ECM) microenvironment occur after myocardial ischemia and reperfusion injury (I/R). 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 HA synthase 2 (Has2) and Has1 were used in a murine model of cardiac I/R. Chemical exchange saturation transfer (CEST) imaging was adapted to image cardiac ECM post I/R. Of note, the cardiac CEST signal was severely suppressed by Has2 deletion and pharmacologic inhibition of HA synthesis 24 hours after I/R. Has2-deficient mice (Has2 KO) 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 to control post I/R. Importantly, in Has2 KO mice cardiac macrophages were diminished following I/R as detected by 19F MRI of perfluorcarbon-labeled immune cells, MAC-2 immunostaining and FACS analysis (CD45+...