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

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. This work was supported by VA Merit Awards BX004836 and RD001363 to D.T.E. Cardiovascular Research Center, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA Jintao Wang, Enming J.

Eitzman Cardiovascular Research Center, University of Michigan, 7301A MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-0644, USA The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.