Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency

Kathryn J Griffin,Laura M Newell,Kingsley R Simpson,Cora M.L Beckers,Mark J Drinkhill,Kristina F Standeven,Lih T Cheah,Siiri E Iismaa,Peter J Grant,Christopher L Jackson,Richard J Pease

doi:10.1016/j.atherosclerosis.2019.12.013

Kathryn J Griffin, Laura M Newell + Show 9 more

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https://doi.org/10.1016/j.atherosclerosis.2019.12.013

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Abstract

Background and aimsTransglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. MethodsAtherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and also in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. ResultsNo difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm2 knockout mice. However, concomitant Tgm2 knockout markedly increased fibrosis, as apparent in both Apoe/Tgm2/F13a1 knockout and Tgm2/F13a1 knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The resulting fibrosis was interstitial in nature and caused only minor changes in cardiac function. ConclusionsThese studies confirm that FXIII-A and TG2 fulfil different roles in the mouse myocardium. FXIII-A protects against vascular leakage while TG2 contributes to the stability or repair of the vasculature. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition.

Highlights

Transglutaminases (TGs) comprise a family of 8 enzymes that catalyse the Ca2+-dependent formation of Nε (γ-glutamyl) lysine isopeptide cross-links between and within protein chains [1].TG2, which is known as tissue transglutaminase, is expressed in all cell-types and in all tissues, but its expression increases under conditions of stress [2]
Fat-feeding is associated with increased mortality in mixed strain, Apoe knockout mice that are deficient in FXIII-A
To determine whether FXIII-A and TG2 act redundantly to influence plaque development and stability, transglutaminase knockout mice were crossed with Apoe knockout mice and subjected to a 12 week period of fat feeding to induce atherosclerosis

Summary

Introduction

Transglutaminases (TGs) comprise a family of 8 enzymes that catalyse the Ca2+-dependent formation of Nε (γ-glutamyl) lysine isopeptide cross-links between and within protein chains [1].TG2, which is known as tissue transglutaminase, is expressed in all cell-types and in all tissues, but its expression increases under conditions of stress [2]. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. Methods: Atherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. Results: No difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition

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Conclusion