Hyaluronan synthase 3 is protective after cardiac ischemia-reperfusion by preserving the T cell response

Matrix Biol. 2022 Sep:112:116-131. doi: 10.1016/j.matbio.2022.08.008. Epub 2022 Aug 23.

Abstract

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 min 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.

Keywords: Extracellular matrix; Hyaluronan synthase 3; Myocardial infarction; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5
  • Coronary Artery Disease*
  • Humans
  • Hyaluronan Synthases / genetics
  • Hyaluronan Synthases / metabolism
  • Hyaluronic Acid / metabolism
  • Isoenzymes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction* / genetics
  • Reperfusion
  • Ventricular Remodeling

Substances

  • Annexin A5
  • Isoenzymes
  • Hyaluronic Acid
  • HAS3 protein, human
  • Has3 protein, mouse
  • Hyaluronan Synthases