PB0020 - The Effects of Hyperglycemia on Endothelial Activation and the Initiation of Atherosclerosis

Background: 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.

Aims: This study examines the effect of hyperglycemia on endothelial cell activation and the initiation and progression of atherosclerosis.

Methods: Human aortic endothelial cells (HAECs) were exposed to control (5 mM) or elevated (30 mM) concentrations of glucose for 24 hours and the expression of adhesive proteins P-selectin, E- selectin, VCAM-1 and ICAM-1 were quantified by RT-PCR. Atherogenesis and adhesion protein expression was quantified by immunostaining cross sections of the ascending aorta of atherosclerosis-prone normoglycemic (ApoE-/-) and hyperglycemic (ApoE-/-Ins2+/Akita) mice.

Results: In vitro studies revealed that exposure of HAECs to 30 mM glucose significantly increased the expression of P-selectin, E- selectin and VCAM-1, but not ICAM-1. In vivo studies showed that, prior to atherosclerotic lesion development, 5-week-old hyperglycemic ApoE-/- Ins2+/akita mice had significantly increased expression of P-selectin, E- selectin and VCAM-1 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 lesions than ApoE-/- controls. 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 with an SGLT2 inhibitor did significantly reduce endothelial activation.

Conclusion(s): Together these findings support a causative role of 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.