Abstract Number: PB0018
Meeting: ISTH 2022 Congress
Background: The mechanisms underlying the different atherosclerosis course in diabetic and non-diabetic patients remain unknown. Hyperglycemia causes endothelial cells dysfunction, a key disease driver. Atherosclerotic plaques display markers of senescence and unfolded protein response (UPR). Plasma levels of coagulation protease, activated protein C decline in diabetes and atherosclerosis.
Aims: Our aim is to study the role activated protein C which is well known for its cytoprotective and anti-inflamamtory functions. We hypothesized that activated protein C prevents diabetes induced accelerated atherosclerosis by reducing maladaptive UPR induced endothelial cell senescence.
Methods: To gain insights into pathomechanisms of diabetes induced atherosclerotic plaque development we cultured human coronary artery endothelial cells (HCAECs) under hyperglycemic (HG) or hyperlipidaemic (HL) conditions. ApoE-/- mice (age 8 weeks) was made either diabetic by streptozotocin injections (A mouse model type 1 diabetes) or fed them HFD to induce hyperlipidemia. Mice were analyzed after 20 weeks of treatments.
Results: HG conditions induced strong barrier disruption as compared to HL (TEER, FITC dextran leakage) and protein expression of the senescence markers (p21, p16, p53) and UPR markers (XBP1, IRE1α and ATF6). Activated protein C restored barrier integrity, reduced glucose induced expression of senescence and UPR markers in vitro. Targeting IRE1α RNAase activity prevented HG induced cellular senescence. Ex vivo, diabetic ApoE-/- mice revealed increased expression of senescence, inflammation and UPR markers within atherosclerotic lesion as compared with non-diabetic ApoE-/- mice.
Conclusion(s): Senescence associated inflammation and UPR are associated with glucose-dependent endothelial cells dysfunction and loss of endothelial barrier integrity. These results demonstrate that diabetes-induced atherosclerosis is associated with cellular senescence and UPR. Targeting cellular senescence and UPR (with aPC or IRE1α inhibitor) may be a useful therapy of atherosclerosis in diabetic patients.
To cite this abstract in AMA style:Fatima S, Gadi I, Ambreen S, Singh K, Gupta A, Elwakiel A, Krishnan S, Methew A, Khawaja H, Kohli S, Isermann B, Shahzad K. Activated protein C reduces maladaptive unfolded protein response (UPR) to ameliorate diabetes-accelerated atherosclerosis [abstract]. https://abstracts.isth.org/abstract/activated-protein-c-reduces-maladaptive-unfolded-protein-response-upr-to-ameliorate-diabetes-accelerated-atherosclerosis/. Accessed September 26, 2022.
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