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- Title
ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis.
- Authors
Fatima, Sameen; Ambreen, Saira; Mathew, Akash; Elwakiel, Ahmed; Gupta, Anubhuti; Singh, Kunal; Krishnan, Shruthi; Rana, Rajiv; Khawaja, Hamzah; Gupta, Dheerendra; Manoharan, Jayakumar; Besler, Christian; Laufs, Ulrich; Kohli, Shrey; Isermann, Berend; Shahzad, Khurrum
- Abstract
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.
- Subjects
DIABETES complications; PROTEINS; ENDOTHELIAL cells; BIOMARKERS; ENDOTHELIUM; COGNITION; ATHEROSCLEROSIS; CELLULAR signal transduction; GENE expression; AGING; ACTIVATED protein C resistance; DESCRIPTIVE statistics; VASCULAR endothelial growth factors; DATA analysis software; MICE
- Publication
Nutrients, 2022, Vol 14, Issue 14, pN.PAG
- ISSN
2072-6643
- Publication type
Article
- DOI
10.3390/nu14142786