ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis

被引：9

作者：

Fatima, Sameen ^{[1
,2
]}

Ambreen, Saira ^{[1
]}

Mathew, Akash ^{[1
]}

Elwakiel, Ahmed ^{[1
]}

Gupta, Anubhuti ^{[1
]}

Singh, Kunal ^{[1
]}

Krishnan, Shruthi ^{[1
]}

Rana, Rajiv ^{[1
]}

Khawaja, Hamzah ^{[1
]}

Gupta, Dheerendra ^{[1
]}

Manoharan, Jayakumar ^{[1
]}

Besler, Christian ^{[3
]}

Laufs, Ulrich ^{[4
]}

Kohli, Shrey ^{[1
]}

Isermann, Berend ^{[1
]}

Shahzad, Khurrum ^{[1
]}

机构：

[1] Univ Hosp, Inst Lab Med Clin Chem & Mol Diagnost, D-04103 Leipzig, Germany

[2] Otto von Guericke Univ, Med Fac, Inst Expt Internal Med, D-39120 Magdeburg, Germany

[3] Univ Leipzig, Leipzig Heart Ctr, Cardiol, D-04289 Leipzig, Germany

[4] Univ Hosp Leipzig, Klin & Poliklin Kardiol, D-04103 Leipzig, Germany

来源：

NUTRIENTS | 2022年 / 14卷 / 14期

关键词：

atherosclerosis; diabetes; senescence; unfolded protein response; endothelial cells; activated protein C; UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; PLAQUE; NEPHROPATHY; PROGRESSION; RESOLUTION; MELLITUS; THERAPY; CELLS; TRIAL;

D O I：

10.3390/nu14142786

中图分类号：

R15 [营养卫生、食品卫生]; TS201 [基础科学];

学科分类号：

100403 ;

摘要：

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we directly compared the effects of high glucose and oxidized LDL, revealing that high glucose induced more pronounced responses in regard to maladaptive unfolded protein response (UPR), senescence, and vascular endothelial cell barrier disruption. Ex vivo, diabetic ApoE(-/-) mice displayed increased levels of senescence and UPR markers within atherosclerotic lesions compared with nondiabetic ApoE(-/-) mice. Activated protein C pretreatment maintained barrier permeability and prevented glucose-induced expression of senescence and UPR markers in vitro. These data suggest that high glucose-induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which-however-can be reversed by aPC. Taken together, current data suggest that reversal of glucose-induced vascular endothelial cell dysfunction is feasible.

引用

页数：15

共 37 条

[1] Unfolded Protein Response (UPR) Controls Major Senescence Hallmarks [J].