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

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.

• Authors: Marco Piroth, Daniel J Gorski, Christian Hundhausen, Anne Petz, Simone Gorressen, Dominik Semmler, Heba Zabri, Sonja Hartwig, Stefan Lehr, Malte Kelm, Christian Jung, Jens W Fischer
• Journal: Matrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 112 Pg. 116-131 (Sep 2022) ISSN: 1569-1802 [Electronic] Netherlands
• PMID: 35998871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

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

Topics

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