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Circ Res. 2019 Mar 27. doi: 10.1161/CIRCRESAHA.118.313285. [Epub ahead of print]

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

Author information

Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University Düsseldorf.
Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf.
Sanford Burnham Prebys Medical Discovery Institute.
Matrix Biology, Benaroya Research Institute at Virginia MasonS.
Molecular Cardiology, Heinrich-Heine-University Düsseldorf.
Institute of Cardiovascular Physiology, Heinrich-Heine-University Düsseldorf.
Cardiovascular Physiology, Heinrich-Heine-University Düsseldorf.
Cardiology, Pulmonary Diseases, and Vascular Medicine, Heinrich-Heine-University Düsseldorf.



Immediate changes in the extracellular matrix (ECM) microenvironment occur after myocardial ischemia and reperfusion injury (I/R).


Aim of this study was to unravel the role of the early hyaluronan (HA)-rich ECM after I/R.


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+CD11b+Ly6G-CD64+F4/80+cells). In contrast to macrophages, cardiac Ly6Chigh - and Ly6Clow monocytes were unaffected post I/R compared to control mice. Mechanistically, inhibition of HA synthesis led to increased macrophage apoptosis in vivo and in vitro. In addition, 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 Acta2 mRNA expression was reduced by inhibition of HA-synthesis and of CD44 signaling. Furthermore, Has2 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.


Increased HA synthesis contributes to post infarct healing by supporting macrophage survival and by promoting the myofibroblast response. Additionally, imaging of cardiac HA by CEST post I/R might have translational value.


extracellular matrix imaging; ischemia reperfusion injury

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