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

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.

Identiferoai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:87858
Date02 November 2023
CreatorsFatima, 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
PublisherMDPI
Source SetsHochschulschriftenserver (HSSS) der SLUB Dresden
LanguageEnglish
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text
Rightsinfo:eu-repo/semantics/openAccess
Relation2786

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