Empagliflozin attenuates traumatic brain injury-induced atherosclerosis and norepinephrine-induced vascular smooth muscle cell responses

Abstract Traumatic brain injury (TBI) is associated with increased long-term cardiovascular risk, but strategies to limit post-traumatic vascular disease are lacking. We tested whether empagliflozin, a sodium-glucose cotransporter 2 inhibitor, attenuates TBI-induced atherosclerosis in apolipoprotein E-deficient mice. Mice on a Western diet underwent controlled cortical impact or sham surgery and received empagliflozin or vehicle for 10 weeks. TBI increased aortic plaque burden, aortic-root lesion size, and blood pressure without changing plasma cholesterol, glucose, insulin, or 8-isoprostane. In vehicle-treated mice plasma norepinephrine was higher after TBI but not significantly elevated in TBI mice treated with empagliflozin. Empagliflozin prevented the TBI-associated increases in blood pressure and atherosclerosis. SGLT2 immunoreactivity was detected in smooth muscle cell-rich plaque regions and in cultured murine vascular smooth muscle cells. In vitro, empagliflozin inhibited norepinephrine-induced smooth muscle cell migration and proliferation. These findings show that empagliflozin attenuates TBI-accelerated atherosclerosis independently of measured systemic metabolic changes. Hemodynamic effects and direct effects on vascular smooth muscle cell responses may contribute to this protection.