Transglutaminase 2 moderates the expansion of mouse abdominal aortic aneurysms

Abstract Objective Previously published work has indicated that transcripts encoding transglutaminase (TG)2 increase markedly in a rat model of abdominal aortic aneurysm. This study determines whether TG2 and the related transglutaminase, factor (F)XIII-A, protect against aortic aneurysm development in mice. Methods C57BL/6J wild-type, Tgm2-/- knockout, F13a1-/- knockout and Tgm2-/-/F13a1-/- double knockout mice were subjected to laparotomy and peri-aortic application of CaCl2. Results Tgm2-/- mice showed slightly greater aortic dilatation at 6 weeks post treatment when compared to wild type. However, vessels from Tgm2-/- mice, but not wild-type mice, continued to dilate up to 6 months post injury and by 24 weeks, a greater number of Tgm2-/- mice had developed aneurysms (16/17 vs 10/19, p=0.008). Laparotomy resulted in a high death rate in F13a1-/- knockout mice, more frequently from cardiac complications than from haemorrhage, but amongst F13a1-/- mice that survived for 6 weeks following CaCl2 treatment, abdominal aortic aneurysm diameter was unaltered relative to wild-type mice. Laparotomy resulted in a higher death rate amongst Tgm2-/-/F13a1-/- double knockout mice, due to an increased frequency of delayed bleeding. Surprisingly, Tgm2-/-/F13a1-/- double knockout mice showed a trend towards decreased dilatation of the aorta 6 weeks post injury, and this finding was replicated in Tgm2-/-/F13a1-/- mice subjected to carotid artery injury. Levels of transcripts encoding TG2 were not increased in the aortas of injured wild-type or F13a1-/- knockout mice relative to uninjured mice, although changes in the levels of other transcripts accorded with previous descriptions of the CaCl2 aneurysm model in mice. Conclusions Knockout of Tgm2, but not F13a1 exacerbates aortic dilatation, suggesting that TG2 confers protection. However, levels of TG2 mRNA are not acutely elevated post-injury. FXIII-A plays a role in preventing postoperative damage following laparotomy, confirming previous reports that it prevents distal organ damage following trauma. TG2 promotes wound healing post-surgery and, in its absence, the bleeding diathesis associated with FXIII-A deficiency is further exposed.