(556.9) Canagliflozin Regulates Human Endothelial Cell Function: Role of Heme Oxygenase-1

Poster Board Number: E101

William Durante (University of Missouri-Columbia), Ghazaleh Behnammanesh (University of Missouri-Columbia), Giovanna Durante (University of Missouri-Columbia), Kelly Peyton (University of Missouri-Columbia)

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the newest class of glucose lowering drugs that act by inhibiting glucose reabsorption in the proximal tubule of the kidney. Recent clinical trials found that SGLT2 inhibitors reduce cardiovascular disease and mortality in patients with diabetes. The mechanism underlying the salutary actions of these drugs is not completely clear; however, it does not involve differential improvements in glycemic control. Given the critical role that endothelial cells (ECs) play in maintaining vascular homeostasis, the present study investigated the effect of the SGLT2 inhibitor canagliflozin on EC function. It also determined if the vasoprotective protein heme oxygenase-1 (HO-1) contributes to the cellular actions of the drug. Treatment of human umbilical vein ECs with clinically relevant concentrations of canagliflozin blocked cell proliferation, and this was associated with a pronounced decline in DNA synthesis. Canagliflozin also inhibited the migration of ECs following scrape injury in a concentration-dependent manner. Incubation of ECs with a high concentration of glucose (25mM) and oxidized low-density lipoprotein (oxLDL;50mg/L), which mimics the diabetic milieu, stimulated the adhesion of monocytes to ECs. However, treatment of ECs with canagliflozin markedly reduced the binding of monocytes to these cells. In addition, canagliflozin increased the expression of HO-1 in a time and concentration-dependent fashion, leading to a significant rise in endothelial HO-1 activity. Finally, inhibition of HO-1 activity or expression increased the adhesion of monocytes to glucose/oxLDL-challenged ECs exposed to canagliflozin but had no effect on the proliferative or migratory response of canagliflozin-treated ECs.  In conclusion, the present study identifies canagliflozin as a key regulator of EC function. Moreover, it demonstrates that the induction of HO-1 by canagliflozin contributes to the anti-inflammatory action the drug. Thus, canagliflozin may exert some of its favorable effects in diabetes by limiting endothelial inflammation via the upregulation of HO-1.

Support or Funding Information

Supported by the National Institutes of Health R01 HL149727 and the American Diabetes Association Grant #1-17-IBS-290.