Abstract
Background: The extracellular matrix (ECM) provides structural and functional support for the myocardium, but myocardial infarction (MI) changes the composition of the ECM. One of the chief components of the ECM, hyaluronan (HA), is elevated after MI; however, specific biological actions of HA—particularly at the level of infiltrating immune cells and implications of such interactions on ventricular remodeling—have not been explored. Goals: Because upregulation of HA coincides with macrophage infiltration after MI, we determined whether hyaluronan interacts with macrophages and investigated the implication of such interactions on macrophage function. Methods: WT mice were subjected to non-reperfused MI to determine changes in hyaluronan synthases (HAS), hyaluronidases (HYAL), and HA levels in the heart. Interaction of HA with macrophages was studied by polarizing bone marrow derived macrophages and analyzing cells by flow cytometry. Next, we characterized the ability of macrophages to metabolize HA by profiling polarized macrophages for HA-metabolizing enzymes, HA receptors, HA-binding proteins, hyaluronidase activity, and phagocytosis. Results: Compared to Sham hearts, MI (n=5/group) augmented the expression of HAS-2 (10-fold, p=0.002) and HYAL-2 (2 to 4-fold, p=0.0004) in the infarct and remote regions of the heart at 5 d post-MI. HA levels (n=8/group) were elevated in the infarct (1 to 2-fold, p=0.0200) and remote (2 to 3-fold, p=0.0007) regions of the heart compared to sham hearts. Polarizing macrophages (n=3/group) in the presence fluorescein-conjugated HA (HA-FL) showed that naïve (M0), pro-inflammatory (M1), and pro-resolving (M2) macrophages interact with HA-FL; M1 showed the highest FITC intensity. Interestingly, exposing macrophages (n=5/group) to HA provoked an inflammatory phenotype, as reflected by enhanced expression of TNFα (4-fold, p=0.0001) and IL-1β (7-fold, p=0.0094) mRNA; HA also enhanced macrophage phagocytosis (0.5-fold, p= 0.0476). Conclusion: Hyaluronan is elevated following MI and can influence macrophage function. Because of the accumulation of hyaluronan and macrophages in the post-MI heart, macrophage-hyaluronan interactions may be a nexus regulating ventricular remodeling.
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