Hyaluronan Synthase 3 is Protective After Cardiac Ischemia-Reperfusion by preserving the T cell Response

• Published in: Matrix biology 2022-09, Vol.112, p.116-131
• Main Authors: Piroth, Marco, Gorski, Daniel J, Hundhausen, Christian, Petz, Anne, Gorressen, Simone, Semmler, Dominik, Zabri, Heba, Hartwig, Sonja, Lehr, Stefan, Kelm, Malte, Jung, Christian, Fischer, Jens W.
• Format: Article
• Language: English
• Subjects: Animals; Annexin A5; Annexin V; Apoptosis; CD25 antigen; CD3 antigen; CD4 antigen; CD44 antigen; CD69 antigen; Cell activation; Cell proliferation; Coronary Artery Disease; CXCR3 protein; Extracellular matrix; Genotypes; Heart; Heart attacks; Humans; Hyaluronan synthase; hyaluronan synthase 3; Hyaluronan Synthases - genetics; Hyaluronan Synthases - metabolism; Hyaluronic acid; Hyaluronic Acid - metabolism; Ischemia; Isoenzymes; Leukocyte migration; Lymphocytes; Lymphocytes T; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial infarction; Myocardial Infarction - genetics; Peripheral blood; Reperfusion; T cells; Ventricular Remodeling
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2022.08.008

•Mice with systemic deletion of hyaluronan synthase 3 (Has3) exhibit adverse cardiac remodeling and impaired heart function in a model of acute myocardial infarction•Detrimental post-infarct outcome in Has3 deficient mice is associated with reduced numbers of cardiac T helper 1 and regulatory T cells•Targeting hyaluronan-matrix to preserve T cell function may be beneficial for patients with myocardial infarction Dysregulated extracellular matrix (ECM) is a hallmark of adverse cardiac remodeling after myocardial infarction (MI). Previous work from our laboratory suggests that synthesis of the major ECM component hyaluronan (HA) may be beneficial for post-infarct healing. Here, we aimed to investigate the mechanisms of hyaluronan synthase 3 (HAS3) in cardiac healing after MI. Mice with genetic deletion of Has3 (Has3 KO) and wildtype mice (WT) underwent 45 minutes of ischemia with subsequent reperfusion (I/R), followed by monitoring of heart function and analysis of tissue remodeling for up to three weeks. Has3 KO mice exhibited impaired cardiac function as evidenced by a reduced ejection fraction. Accordingly, Has3 deficiency also resulted in an increased scar size. Cardiac fibroblast activation and CD68+ macrophage counts were similar between genotypes. However, we found a significant decrease in CD4 T cells in the hearts of Has3 KO mice seven days post-MI, in particular reduced numbers of CD4+CXCR3+ Th1 and CD4+CD25+ Treg cells. Furthermore, Has3 deficient cardiac T cells were less activated and more apoptotic as shown by decreased CD69+ and increased annexin V+ cells, respectively. In vitro assays using activated splenic CD3 T cells demonstrated that Has3 deficiency resulted in reduced expression of the main HA receptor CD44 and diminished T cell proliferation. T cell transendothelial migration was similar between genotypes. Of note, analysis of peripheral blood from patients with ST-elevation myocardial infarction (STEMI) revealed that HAS3 is the predominant HAS isoenzyme also in human T cells. In conclusion, our data suggest that HAS3 is required for mounting a physiological T cell response after MI to support cardiac healing. Therefore, our study may serve as a foundation for the development of novel strategies targeting HA-matrix to preserve T cell function after MI.