Transglutaminase 2 moderates the expansion of mouse abdominal aortic aneurysms

Objective: Previously published work has indicated that transcripts encoding transglutaminase 2 (TG2) increase markedly in a rat model of abdominal aortic aneurysm. This study determines whether TG2 and the related TG, factor XIII-A (FXIII-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 periaortic application of CaCl₂.

Results: Tgm2 ^-/- mice showed slightly greater aortic dilatation at 6 weeks after treatment when compared with wild type. However, vessels from Tgm2 ^-/- mice, but not wild-type mice, continued to dilate up to 6 months after injury and by 24 weeks, a greater number of Tgm2 ^-/- mice had developed aneurysms (16/17 vs 10/19; P = .008). Laparotomy resulted in a high death rate in F13a1 ^-/- knockout mice, more frequently from cardiac complications than from hemorrhage, but among F13a1 ^-/- mice that survived for 6 weeks after CaCl₂ treatment, abdominal aortic aneurysm diameter was unaltered relative to wild-type mice. Laparotomy resulted in a higher death rate among Tgm2 ^-/- /F13a1 ^-/- double knockout mice, owing to an increased frequency of delayed bleeding. Surprisingly, Tgm2 ^-/- /F13a1 ^-/- double knockout mice showed a trend toward decreased dilatation of the aorta 6 weeks after 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 messenger RNA are not acutely elevated after injury. FXIII-A plays a role in preventing postoperative damage after laparotomy, confirming previous reports that it prevents distal organ damage after trauma. TG2 promotes wound healing after surgery and, in its absence, the bleeding diathesis associated with FXIII-A deficiency is further exposed.