Peptidylarginine Deiminase 2 Knockout Improves Survival in Hemorrhagic Shock.
Peptidylarginine Deiminase 2 Knockout Improves Survival in Hemorrhagic Shock.
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DOI：
10.1097/shk.0000000000001489
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发表时间：
2019-11
期刊：
影响因子：
3.1
通讯作者：
Jing Zhou;Ben E. Biesterveld;Yongqing Li;Zhenyu Wu;Yuzi Tian;Aaron M Williams;Shuo Tian;Wenbin Gao
中科院分区：
文献类型：
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作者：
Jing Zhou;Ben E. Biesterveld;Yongqing Li;Zhenyu Wu;Yuzi Tian;Aaron M Williams;Shuo Tian;Wenbin Gao
肽基精氨酸脱亚胺酶（PAD）家族通过瓜氨酸蛋白将精氨酸转化为瓜氨酸。PAD 2和PAD 4抑制剂可改善出血性休克（HS）的存活率。然而，尚未研究同种型特异性PAD抑制对改善存活率的影响。在这项研究中，我们利用选择性Pad 2基因敲除（KO）小鼠来阐明PAD 2功能的丧失导致HS中的促存活作用。方法HS：Pad 2和野生型（WT）小鼠（n = 5/组）经受致死HS（55%体积出血）。在7天内监测存活率。心肌梗死（MI）：通过永久性LAD结扎使Pad 2和WT小鼠（n = 9/组）经受MI以检查缺血对心脏的影响。24小时后测量心功能和梗死面积。结果HS：Pad 2小鼠表现出100%的存活率，而WT小鼠为0%（p = 0.002）。在亚致死HS模型中，24小时后Pad 2中的心脏β-连环蛋白水平高于WT。MI：WT小鼠表现出与Pad 2（60%）相比更大的MI（75%）（p < 0.05）。与WT相比，Pad 2具有显著更高的射血分数和缩短分数（p < 0.05）。结论Pad 2可提高致死性HS的存活率。PAD 2功能丧失改善存活的可能机制包括细胞存活途径的激活、改善的心脏缺血耐受性和改善的缺血期间的心脏功能。PAD 2有望成为HS和心肌缺血的治疗靶点。
BACKGROUND The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2 knockout (KO) mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS. METHODS HS: Pad2 and wild type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over seven days. Myocardial infarction (MI): Pad2 and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 hours cardiac function and infarct size were measured. RESULTS HS: Pad2 mice demonstrated 100% survival compared to 0% for WT mice (p = 0.002). In a sub-lethal HS model, cardiac β-catenin levels were higher in Pad2 compared to WT after 24 hours. MI: WT mice demonstrated larger MI (75%) compared to Pad2 (60%) (p < 0.05). Pad2 had significantly higher ejection fraction and fractional shortening compared to WT (p < 0.05). CONCLUSIONS Pad2 improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improve survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.