Department of Anesthesiology and Cardiology, Yanbian University Hospital, 1327 Juzi Street, Yanji, Jilin 133000, P.R. China.
State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union, Medical College, 167 Beilishi Road, Xicheng District, Beijing 100037, P.R. China.
Exp Anim. 2021 Nov 10;70(4):541-552. doi: 10.1538/expanim.21-0067. Epub 2021 Jul 5.
Exposure to chronic psychosocial stress is a risk factor for various pulmonary diseases. In view of the essential role of dipeptidyl peptidase 4 (DPP4) in animal and human lung pathobiology, we investigated the role of DPP4 in stress-related lung injury in mice. Eight-week-old male mice were randomly divided into a non-stress group and a 2-week immobilization stress group. Non-stress control mice were left undisturbed. The mice subjected to immobilized stress were randomly assigned to the vehicle or the DPP4 inhibitor anagliptin for 2 weeks. Chronic stress reduced subcutaneous and inguinal adipose volumes and increased blood DPP4 levels. The stressed mice showed increased levels in the lungs of genes and/or proteins related to oxidative stress (p67, p47, p22 and gp91), inflammation (monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), apoptosis (caspase-3, -8, -9), senescence (p16, p21, and p53) and proteolysis (matrix metalloproteinase-2 to -9, cathepsin S/K, and tissue inhibitor of matrix metalloproteinase-1 and -2), and reduced levels of eNOS, Sirt1, and Bcl-2 proteins; and these effects were reversed by genetic and pharmacological inhibitions of DPP4. We then exposed human umbilical vein endothelial cells in vitro to hydrogen peroxide; anagliptin treatment was also observed to mitigate oxidative and inflammatory molecules in this setting. Anagliptin can improve lung injury in stressed mice, possibly by mitigating vascular inflammation, oxidative stress production, and proteolysis. DPP4 may become a new therapeutic target for chronic psychological stress-related lung disease in humans and animals.
慢性心理社会应激是各种肺部疾病的危险因素。鉴于二肽基肽酶 4（DPP4）在动物和人类肺部病理生物学中的重要作用，我们研究了 DPP4 在应激相关肺部损伤中的作用。将 8 周龄雄性小鼠随机分为非应激组和 2 周束缚应激组。非应激对照小鼠未受干扰。应激组小鼠随机分为载体或 DPP4 抑制剂安格列汀组，持续 2 周。慢性应激导致皮下和腹股沟脂肪体积减少，血液 DPP4 水平升高。应激小鼠肺部的基因和/或与氧化应激（p67、p47、p22 和 gp91）、炎症（单核细胞趋化蛋白-1、血管细胞黏附分子-1 和细胞间黏附分子-1）、细胞凋亡（caspase-3、-8、-9）、衰老（p16、p21 和 p53）和蛋白水解（基质金属蛋白酶-2 至-9、组织蛋白酶 S/K 和基质金属蛋白酶组织抑制剂-1 和-2）相关的基因和蛋白水平升高，eNOS、Sirt1 和 Bcl-2 蛋白水平降低；这些作用通过 DPP4 的遗传和药理学抑制得到逆转。随后，我们在体外将人脐静脉内皮细胞暴露于过氧化氢中；也观察到安格列汀治疗可减轻这种情况下的氧化和炎症分子。安格列汀可以改善应激小鼠的肺损伤，可能通过减轻血管炎症、氧化应激产生和蛋白水解。DPP4 可能成为人类和动物慢性心理应激相关肺部疾病的新治疗靶点。
