Canagliflozin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration

Abstract

Cardiovascular disease is the major cause of morbidity and mortality in diabetes. Although numerous factors contribute to the development of diabetes‐associated cardiovascular disease, excessive proliferation and migration of vascular smooth muscle cells (SMCs) plays a critical role. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are the latest approved class of glucose lowering drugs. By blocking glucose uptake in the proximal tubule of the kidney, SGLT2 inhibitors induce glycosuria leading to decreases in fasting and postprandial glycemia. Notably, large multicenter clinical trials have demonstrated that SGLT2 inhibitors reduce cardiovascular disease and mortality in patients with type 2 diabetes. The mechanism underlying the cardiovascular benefits of SGLT2 inhibitors is not fully known; however, direct effects on vascular SMCs have not been considered. In the present study, we investigated the effect of three different SGLT2 inhibitors on vascular SMC function. Treatment of rat and human aortic SMCs with canagliflozin resulted in a potent, concentration‐dependent inhibition of cell proliferation and DNA synthesis. The anti‐proliferative effect of canagliflozin was observed at clinically relevant concentrations, and this was not seen with other SGLT2 inhibitors, including empagliflozin and dapagliflozin. The inhibition of SMC growth by canagliflozin occurred in the absence of cell death and was associated with the arrest of SMCs in the G0/G1 phase of the cell cycle. In addition, scratch‐wound assays found that vascular SMC migration was blocked by canagliflozin in a concentration‐dependent manner, whereas empagliflozin or dapagliflozin had no effect on SMC motility. In conclusion, the present study identified canagliflozin as a robust inhibitor of vascular SMC proliferation and migration. These inhibitory effects of canagliflozin are detected at pharmacologically relevant concentrations and are unique for this drug and not seen with other SGLT2 inhibitors. The ability of canagliflozin to exert these pleiotropic effects on vascular SMC function may contribute to the salutary cardiovascular actions of this drug in patients with type 2 diabetes.Support or Funding InformationSupported by American Diabetes Association grant #1‐17‐IBS‐290.