The Effects of Hyperglycemia on Early Endothelial Activation and the Initiation of Atherosclerosis

It is well established that patients with diabetes have an increased risk of developing atherosclerotic Cardiovascular Disease. The earliest detectable sign of atherosclerosis initiation is endothelial cell activation. Activated endothelial cells express adhesion proteins, P-Selectin, E-Selectin, vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1, that function to recruit monocytes to the subendothelial layer. This study examines the effect of hyperglycemia on endothelial cell activation and the initiation and progression of atherosclerosis. In vitro studies revealed that exposure of human aortic endothelial cells to elevated (30mM) glucose concentrations significantly increased the expression of P-Selectin, E-Selectin and VCAM-1. In vivo studies showed that, prior to lesion development, 5-week-old hyperglycemic ApoE^-/-Ins2^+/akita mice had significantly increased expression of these adhesion proteins in the aortic sinus and increased macrophage infiltration, compared to normoglycemic ApoE^-/- controls. At 25 weeks of age, ApoE^-/-Ins2^+/akita mice had significantly larger atherosclerotic plaques than ApoE^-/- controls (0.022mm³±0.004 vs 0.007mm³±0.001, P<0.05). Similar endothelial activation was observed in heterozygous ApoE^+/-Ins2^+/akita mice, however detectable atherosclerotic lesions did not develop in the absence of dyslipidemia. Lowering blood glucose levels (by 55%) using an SGLT2 Inhibitor did reduce endothelial activation. Together these findings support a causative role for hyperglycemia in the early initiation of atherogenesis and highlight the importance of blood glucose regulation as a strategy to prevent, and perhaps reverse, atherosclerotic CVD.