Format

Send to

Choose Destination
Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1614-1628. doi: 10.1161/ATVBAHA.119.312659. Epub 2019 Jul 11.

SGLT-2 (Sodium-Glucose Cotransporter 2) Inhibition Reduces Ang II (Angiotensin II)-Induced Dissecting Abdominal Aortic Aneurysm in ApoE (Apolipoprotein E) Knockout Mice.

Author information

1
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.).
2
CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research-ISCIII, Madrid, Spain (H.G.-N., M.J.S., J.T.R., L.P.).
3
Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain (M.J.S., L.P.).
4
Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Spain (J.T.R.).

Abstract

OBJECTIVE:

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.

CONCLUSIONS:

Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.

KEYWORDS:

angiotensin II; animals; aortic aneurysm, abdominal; inflammation; sodium-glucose cotransporter type-2

PMID:
31294626
DOI:
10.1161/ATVBAHA.119.312659

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center