Griffin Kathryn J, Simpson Kingsley R, Beckers Cora M L, Newell Laura M, Cheah Lih T, Yuldasheva Nadira Y, Iismaa Siiri, Jackson Christopher L, Scott Julian D A, Pease Richard J
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
Bristol Heart Institute, University of Bristol, Bristol, UK.
JVS Vasc Sci. 2021 May 18;2:95-109. doi: 10.1016/j.jvssci.2021.04.002. eCollection 2021.
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.
C57BL/6J wild-type, knockout, knockout, and / double knockout mice were subjected to laparotomy and periaortic application of CaCl.
mice showed slightly greater aortic dilatation at 6 weeks after treatment when compared with wild type. However, vessels from mice, but not wild-type mice, continued to dilate up to 6 months after injury and by 24 weeks, a greater number of mice had developed aneurysms (16/17 vs 10/19; = .008). Laparotomy resulted in a high death rate in knockout mice, more frequently from cardiac complications than from hemorrhage, but among mice that survived for 6 weeks after CaCl treatment, abdominal aortic aneurysm diameter was unaltered relative to wild-type mice. Laparotomy resulted in a higher death rate among / double knockout mice, owing to an increased frequency of delayed bleeding. Surprisingly, / double knockout mice showed a trend toward decreased dilatation of the aorta 6 weeks after injury, and this finding was replicated in / mice subjected to carotid artery injury. Levels of transcripts encoding TG2 were not increased in the aortas of injured wild-type or knockout mice relative to uninjured mice, although changes in the levels of other transcripts accorded with previous descriptions of the CaCl aneurysm model in mice.
Knockout of , but not 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.
先前发表的研究表明，在腹主动脉瘤大鼠模型中，编码转谷氨酰胺酶2（TG2）的转录物显著增加。本研究旨在确定TG2和相关的凝血因子ⅩⅢA（FXIII-A）是否能预防小鼠主动脉瘤的发生。
对C57BL/6J野生型、TG2基因敲除、FXIII-A基因敲除以及TG2/FXIII-A双基因敲除小鼠进行剖腹手术，并在主动脉周围应用氯化钙。
与野生型小鼠相比，TG2基因敲除小鼠在治疗后6周时主动脉扩张略明显。然而，TG2基因敲除小鼠的血管在损伤后6个月内持续扩张，而野生型小鼠则无此现象。到24周时，更多的TG2基因敲除小鼠发生了动脉瘤（16/17比10/19；P = 0.008）。剖腹手术导致TG2基因敲除小鼠死亡率较高，更多是死于心脏并发症而非出血，但在氯化钙治疗后存活6周的TG2基因敲除小鼠中，腹主动脉瘤直径与野生型小鼠相比未发生改变。剖腹手术导致TG2/FXIII-A双基因敲除小鼠死亡率更高，原因是延迟出血的频率增加。令人惊讶的是，TG2/FXIII-A双基因敲除小鼠在损伤后6周时主动脉扩张有减小的趋势，这一发现也在接受颈动脉损伤的TG2/FXIII-A双基因敲除小鼠中得到了验证。与未受伤小鼠相比，受伤的野生型或TG2基因敲除小鼠主动脉中编码TG2的转录物水平并未升高，尽管其他转录物水平的变化与先前对小鼠氯化钙动脉瘤模型的描述一致。
敲除TG2基因而非FXIII-A基因会加剧主动脉扩张，这表明TG2具有保护作用。然而，损伤后TG2信使核糖核酸水平并未急剧升高。FXIII-A在预防剖腹手术后的损伤中起作用，证实了先前的报道，即它能预防创伤后远端器官损伤。TG2促进手术后伤口愈合，缺乏TG2时，与FXIII-A缺乏相关的出血素质会进一步显现。
