Effects of Empagliflozin on Vascular and Skeletal Mineralization in Hyperlipidemic Mice

Sophia Kalanski; Stuti Pradhan; Andy Hon; Yuxuan Xia; Nora Safvati; Juan Carlos Rivera; Mimi Lu; Linda L Demer; Yin Tintut

doi:10.1016/j.vph.2024.107376

Effects of Empagliflozin on Vascular and Skeletal Mineralization in Hyperlipidemic Mice

Vascul Pharmacol. 2024 Apr 30:155:107376. doi: 10.1016/j.vph.2024.107376. Online ahead of print.

Authors

Sophia Kalanski¹, Stuti Pradhan¹, Andy Hon¹, Yuxuan Xia¹, Nora Safvati¹, Juan Carlos Rivera², Mimi Lu¹, Linda L Demer³, Yin Tintut⁴

Affiliations

¹ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
² Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, California, USA.
³ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA; Department of Physiology, University of California, Los Angeles, Los Angeles, California, USA.
⁴ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA; Department of Physiology, University of California, Los Angeles, Los Angeles, California, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, California, USA. Electronic address: ytintut@mednet.ucla.edu.

PMID: 38692418
DOI: 10.1016/j.vph.2024.107376

Abstract

Cardiovascular disease and osteoporosis, major causes of morbidity and mortality, are associated with hyperlipidemia. Recent studies show that empagliflozin (EMPA), an inhibitor of sodium-glucose cotransporter-2 (SGLT2), improves cardiovascular health. In preclinical animal studies, EMPA mitigates vascular calcification in the males but its effects in the females are not known. Thus, we used female mice to test the effects of EMPA on calcification in the artery wall, cardiac function, and skeletal bone. By serial in vivo microCT imaging, we followed the progression of aortic calcification and bone mineral density in young and older female Apoe^-/- mice fed a high-fat diet with or without EMPA. The two different age groups were used to compare early vs. advanced stages of aortic calcification. Results show that EMPA treatment increased urine glucose levels. Aortic calcium content increased in both the controls and the EMPA-treated mice, and EMPA did not affect progression of aortic calcium content in both young and older mice. However, 3-D segmentation analysis of aortic calcium deposits on microCT images revealed that EMPA-treated mice had significantly less surface area and volume of calcified deposits as well as fewer numbers of deposits than the control mice. To test for direct effects on vascular cell calcification, we treated murine aortic smooth muscle cells with EMPA, and results showed a slight inhibition of alkaline phosphatase activity and inflammatory matrix calcification. As for skeletal bone, EMPA-treated mice had significantly lower BMD than the controls in both the lumbar vertebrae and femoral bones in both young and older mice. The findings suggest that, in hyperlipidemic female mice, unlike males, SGLT2 inhibition with empagliflozin does not mitigate progression of aortic calcification and may even lower skeletal bone density.

Keywords: Empagliflozin; Hyperlipidemia; SGLT2.