Vascular disease is the major cause of mortality in diabetes. Although many factors contribute to diabetes-associated vascular disease, inflammation of endothelial cells (ECs) plays a critical role. Sodium-glucose transporter 2 (SGLT2) inhibitors are recently approved anti-hyperglycemic drugs that cause a significant reduction in cardiovascular events in type 2 diabetic patients, but the mechanisms underlying this protection are not fully known. In the present study, we investigated the effect of SGLT2 inhibitors on the expression of the vasoprotective protein heme oxygenase-1 (HO-1) in human umbilical vein ECs. Treatment of ECs with canagliflozin, dapagliflozin, or empagliflozin stimulated the expression of HO-1 mRNA and protein; however, only clinically achievable concentrations of canagliflozin (3-10µM) increased HO-1 levels. The induction of HO-1 by canagliflozin was associated with an increase in Nrf2 activity and reactive oxygen species (ROS) formation. Canagliflozin also stimulated HO-1 promoter activity, and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. In addition, the canagliflozin-mediated induction of HO-1 was abolished by N-acetyl-L-cysteine or rotenone. Significantly, prior treatment of ECs with canagliflozin inhibited the induction of the adhesion molecules ICAM-1 and VCAM-1 in response to high concentrations of glucose (25mM) and oxidized low-density lipoprotein (50mg/L) that mimic the diabetic milieu. Significantly, the anti-inflammatory action of canagliflozin was abrogated by blocking HO-1 activity or expression.
In conclusion, this study demonstrates that canagliflozin stimulates HO-1 gene expression in the vascular endothelium via the ROS-Nrf2 pathway, and that canagliflozin mitigates inflammation in human ECs exposed to a diabetic environment via the induction of HO-1. Thus, canagliflozin may exert some of it cardiovascular benefit in diabetes by targeting HO-1.
K.J. Peyton: None. G. Behnammanesh: None. W. Durante: None.