Dapagliflozin Ameliorates the Formation and Progression of Experimental Abdominal Aortic Aneurysms by Reducing Aortic Inflammation in Mice

Abstract

Background. Dapagliflozin, a sodium glucose transporter protein-2 (SGLT-2) inhibitor, reduces the risk for cardiovascular diseases. However, the influence of dapagliflozin on nondissecting abdominal aortic aneurysms (AAAs) remains unclear. Methods. AAAs were created in male C57BL/6 mice via intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were daily treated with dapagliflozin (1 or 5 mg/kg body weight) or an equal volume of vehicle through oral gavage beginning one day prior to PPE infusion for 14 days. To investigate its translational value, dapagliflozin or vehicle was also administered to mice with existing AAAs in another cohort. Aortic diameters were measured prior to (day 0 for baseline) and 14 days after PPE infusion. After sacrifice, mice aortae were collected, and following histological analyses were performed. Results. Dapagliflozin treatment significantly reduced aneurysmal aortic expansion following PPE infusion as compared to vehicle treatment especially at 5 mg/kg body weight (approximately 21% and 33% decreases in 1 and 5 mg/kg treatment groups, respectively). The dose-dependent attenuation of AAAs by dapagliflozin was also confirmed on histological analyses. Dapagliflozin remarkably reduced aortic accumulation of macrophages, CD4+ T cells, and B cells particularly following dapagliflozin treatment at 5 mg/kg. Dapagliflozin treatment also markedly attenuated medial SMC loss. Though the difference was not significant, dapagliflozin treatment tended to attenuate CD8+ T cells and elastin degradation. Dapagliflozin treatment at 5 mg/kg caused a 53% reduction in neovessel density. Furthermore, dapagliflozin treatment mitigated further progress of existing AAAs. Conclusion. Dapagliflozin treatment ameliorated PPE-induced AAAs by inhibiting aortic leukocytes infiltration and angiogenesis.

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

“…In apolipoprotein E-deficient (ApoE −/− ) mice with T2DM induced with streptozotocin (STZ), dapagliflozin treatment can attenuate atherosclerosis lesions and decrease atherosclerotic macrophage infiltration [ 170 , 171 ], an effect also observed in ApoE −/− mice fed with a high-fat diet [ 172 ], in a normoglycemic rabbit model of atherosclerosis [ 173 ], in LDL-receptor-deficient (Ldlr −/− ) mice with a high-fat and high-sucrose diabetogenic diet [ 174 ], or in T2DM rats [ 175 ]. Moreover, in mice with abdominal aortic aneurysms, dapagliflozin reduces the risk and progression of small aneurysms in part by attenuating aortic wall macrophage infiltration [ 176 ].…”

Genetic deficiency of protein inhibitor of activated STAT3 suppresses experimental abdominal aortic aneurysms

“…MMP2 and MMP9 are contributors of PPE-induced AAAs ( 17 , 22 , 23 ). The levels of aortic MMP2 and MMP 9 were diminished in PIAS3 −/− as compared to PIAS3 +/+ mice ( Figure 3A ).…”

“…Experimental AAAs were induced in PIAS3 −/− and PIAS3 +/+ mice by transient luminal infusion of porcine pancreatic elastase (PPE, 1.5 units/mL in phosphate-buffered saline) in controlled infrarenal aortic segment as previously reported ( 16 , 17 ). Briefly, 9–12 weeks old male mice were anesthetized by 2% isoflurane inhalation, and infrarenal aorta was exposed via a laparotomy.…”

Double-edged sword of diabetes mellitus for abdominal aortic aneurysm

“…Empagliflozin blunted p38 MAPK and NF-kB phosphorylation, thereby restricting AAA growth (80). Another study discovered that dapagliflozin markedly impairs medial SMC loss and alleviated aneurysmal aortic expansion in mice treated with intra-aortic porcine pancreatic elastase (PPE) infusion (54).…”