Introduction:Diabetes Mellitus is hallmarked by accelerated atherosclerosis, which is the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation.

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 (oxLDL) conditions for 48 h. ApoE-/- mice (age 8 weeks) was made either diabetic by streptozotocin injections (A mouse model of type 1 diabetes) or fed them HFD to induce hyperlipidemia. Mice were analyzed after 20 weeks of treatments.

Results: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 revealed increased expression of senescence and UPR markers within atherosclerotic lesion as compared with nondiabetic ApoE-/- mice. Activated protein C restored barrier integrity and reduced glucose induced expression of senescence and UPR markersin vitro. Inhibition of IRE1α(inositol-requiring enzyme 1 alpha), a key UPR activator, prevented glucose induced endothelial barrier disruption and cellular senescence. Conversely, an activator of IRE1 α's RNAase domain recapitulated hyperglycaemia-induced effects, suggesting that hyperglycaemia-induced IRE1αRNAse activity is sufficient to induce senescence and vascular dysfunction.

conclusion:thesis data suggest that high glucose induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which —however—can be reversed by aPC. This suggests that reversal of glucose-induced vascular endothelial cell dysfunction is feasible.

Keywords:Unfolded protein response, activated protein C, human coronary artery Endothelial cells, thrombomodulin, diabetes mellitus.