RÉSUMÉ
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.
Sujet(s)
Composés benzhydryliques , Densité osseuse , Modèles animaux de maladie humaine , Glucosides , Hyperlipidémies , Souris invalidées pour les gènes ApoE , Inhibiteurs du cotransporteur sodium-glucose de type 2 , Calcification vasculaire , Microtomographie aux rayons X , Animaux , Glucosides/pharmacologie , Composés benzhydryliques/pharmacologie , Femelle , Inhibiteurs du cotransporteur sodium-glucose de type 2/pharmacologie , Calcification vasculaire/anatomopathologie , Calcification vasculaire/traitement médicamenteux , Calcification vasculaire/prévention et contrôle , Calcification vasculaire/métabolisme , Hyperlipidémies/traitement médicamenteux , Densité osseuse/effets des médicaments et des substances chimiques , Aorte/effets des médicaments et des substances chimiques , Aorte/anatomopathologie , Aorte/métabolisme , Aorte/imagerie diagnostique , Aorte/physiopathologie , Maladies de l'aorte/anatomopathologie , Maladies de l'aorte/métabolisme , Maladies de l'aorte/prévention et contrôle , Maladies de l'aorte/traitement médicamenteux , Maladies de l'aorte/physiopathologie , Maladies de l'aorte/imagerie diagnostique , Souris de lignée C57BL , Alimentation riche en graisse , Souris , Facteurs âges , Cellules cultivéesRÉSUMÉ
Peripheral serotonin levels are associated with cardiovascular disease risk. We previously found that serum serotonin levels are higher in hyperlipidemic mice than wild-type mice. Evidence also suggests that serotonin regulates biomineralization, in that serotonin treatment augments TNF-a-induced matrix calcification of aortic valve interstitial cells and that a selective inhibitor of peripheral serotonin, LP533401, rescues bone loss induced by ovariectomy in mice. Thus, in the present study, we examined the effects of LP533401 on both skeletal bone mineral density (BMD) and aortic calcification in both young and older hyperlipidemic mice susceptible to calcific atherosclerosis and bone loss. By serial in vivo microCT imaging, we assessed BMD and aortic calcification of Apoe-/- mice fed an atherogenic (high cholesterol) diet alone or mixed with LP533401. Results show that in the young mice, LP533401 blunted skeletal bone loss in lumbar vertebrae but not in femurs. LP533401 also blunted the initial development of aortic calcification but not its progression. Echocardiographic analysis showed that LP533401 blunted both hyperlipidemia-induced cardiac hypertrophy and left ventricular dysfunction. In the older mice, LP533401 increased the BMD of lumbar vertebrae but not of femurs. The aortic calcification progressed in both controls and LP533401-treated mice, but, at post-treatment, LP533401-treated mice had significantly less aortic calcification than the controls. These findings suggest that LP533401 mitigates adverse effects of hyperlipidemia on skeletal and vascular tissues in site- and stage-dependent manners.