From the Institute of Health Research-INCLIVA, Valencia, Spain (R.O., A.C., F.S., H.G.-N., M.J.S., J.T.R., L.P.).
CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research-ISCIII, Madrid, Spain (H.G.-N., M.J.S., J.T.R., L.P.).
Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1614-1628. doi: 10.1161/ATVBAHA.119.312659. Epub 2019 Jul 11.
Abdominal aortic aneurysm (AAA) is a pathological condition of permanent vessel dilatation that predisposes to the potentially fatal consequence of aortic rupture. SGLT-2 (sodium-glucose cotransporter 2) inhibitors have emerged as powerful pharmacological tools for type 2 diabetes mellitus treatment. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events and have beneficial effects on several vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. This study evaluates the effect of oral chronic treatment with empagliflozin-an SGLT-2 inhibitor-on dissecting AAA induced by Ang II (angiotensin II) infusion in apoE (apolipoprotein E) mice. Approach and Results: Empagliflozin treatment significantly reduced the Ang II-induced increase in maximal suprarenal aortic diameter in apoE mice independently of blood pressure effects. Immunohistochemistry analysis revealed that empagliflozin diminished Ang II-induced elastin degradation, neovessel formation, and macrophage infiltration at the AAA lesion. Furthermore, Ang II infusion resulted in a marked increase in the expression of chemokines (CCL-2 [chemokine (C-C motif) ligand 2] and CCL-5 [chemokine (C-C motif) ligand 5]), VEGF (vascular endothelial growth factor), and MMP (matrix metalloproteinase)-2 and MMP-9 in suprarenal aortic walls of apoE mice, and all were reduced by empagliflozin cotreatment. Western blot analysis revealed that p38 MAPK (p38 mitogen-activated protein kinase) and NF-κB (nuclear factor-κB) activation was also reduced in the suprarenal aortas of apoE mice cotreated with empagliflozin. Finally, in vitro studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of proinflammatory chemokines.
Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.
腹主动脉瘤（AAA）是一种永久性血管扩张的病理状态，易导致主动脉破裂这一潜在致命后果。SGLT-2（钠-葡萄糖协同转运蛋白 2）抑制剂已成为治疗 2 型糖尿病的有力药理学工具。除了降低血糖的作用外，最近的研究表明 SGLT-2 抑制剂可减少心血管事件，并对动脉粥样硬化等多种血管疾病具有有益作用；然而，SGLT-2 抑制对 AAA 的潜在影响尚不清楚。本研究评估了口服慢性给予恩格列净（一种 SGLT-2 抑制剂）对 Ang II（血管紧张素 II）输注诱导的载脂蛋白 E（apoE）小鼠腹主动脉瘤的影响。
恩格列净治疗可显著降低 Ang II 诱导的 apoE 小鼠最大肾上腹主动脉直径的增加，独立于血压效应。免疫组织化学分析显示，恩格列净可减少 Ang II 诱导的弹性蛋白降解、新血管形成和 AAA 病变中的巨噬细胞浸润。此外，Ang II 输注导致 apoE 小鼠肾上腹主动脉壁中趋化因子（CCL-2[趋化因子（C-C 基元）配体 2]和 CCL-5[趋化因子（C-C 基元）配体 5]）、VEGF（血管内皮生长因子）和 MMP（基质金属蛋白酶）-2 和 MMP-9 的表达显著增加，而这些均被恩格列净共同处理所减少。Western blot 分析显示，恩格列净共同处理还可降低 apoE 小鼠肾上主动脉中 p38 MAPK（p38 丝裂原活化蛋白激酶）和 NF-κB（核因子-κB）的激活。最后，在体外人主动脉内皮细胞和巨噬细胞研究中，恩格列净抑制白细胞-内皮细胞相互作用和促炎趋化因子的释放。
恩格列净通过抑制 SGLT-2 抑制 AAA 的形成。SGLT-2 抑制可能是预防 AAA 进展的一种新的有前途的治疗策略。
