Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice

Jan Pennig,Philipp Scherrer,Dennis Wolf,Christoph Bode,Ira J Goldberg,Nathaly Anto-Michel,Adam Mullick,Andreas Zirlik,Florian Willecke,Ingo Hilgendorf,Lisa Füner,Peter Stachon,Carmen Härdtner,Mark Colin Gissler,Natalie Hoppe

doi:10.1038/s41598-019-54224-9

Abstract

Diabetes worsens atherosclerosis progression and leads to a defect in repair of arteries after cholesterol reduction, a process termed regression. Empagliflozin reduces blood glucose levels via inhibition of the sodium glucose cotransporter 2 (SGLT-2) in the kidney and has been shown to lead to a marked reduction in cardiovascular events in humans. To determine whether glucose lowering by empagliflozin accelerates atherosclerosis regression in a mouse model, male C57BL/6J mice were treated intraperitoneally with LDLR- and SRB1- antisense oligonucleotides and fed a high cholesterol diet for 16 weeks to induce severe hypercholesterolemia and atherosclerosis progression. At week 14 all mice were rendered diabetic by streptozotocin (STZ) injections. At week 16 a baseline group was sacrificed and displayed substantial atherosclerosis of the aortic root. In the remaining mice, plasma cholesterol was lowered by switching to chow diet and treatment with LDLR sense oligonucleotides to induce atherosclerosis regression. These mice then received either empagliflozin or vehicle for three weeks. Atherosclerotic plaques in the empagliflozin treated mice were significantly smaller, showed decreased lipid and CD68+ macrophage content, as well as greater collagen content. Proliferation of plaque resident macrophages and leukocyte adhesion to the vascular wall were significantly decreased in empagliflozin-treated mice. In summary, plasma glucose lowering by empagliflozin improves plaque regression in diabetic mice.

Highlights

Diabetes worsens atherosclerosis progression and leads to a defect in repair of arteries after cholesterol reduction, a process termed regression
We used a combination of two antisense oligonucleotides (ASO) and a high cholesterol diet (HCD) to induce severe hypercholesterolemia (>600 mg/dl), comparable to commonly used knock-out mouse models of atherosclerosis
After additional induction of STZ-diabetes, plasma cholesterol and plasma glucose increased to 862 ± 37 mg/dl and 356 ± 22 mg/dl, respectively at 16 weeks (Fig. 1B)

Summary

Introduction

Diabetes worsens atherosclerosis progression and leads to a defect in repair of arteries after cholesterol reduction, a process termed regression. To determine whether glucose lowering by empagliflozin accelerates atherosclerosis regression in a mouse model, male C57BL/6J mice were treated intraperitoneally with LDLR- and SRB1- antisense oligonucleotides and fed a high cholesterol diet for 16 weeks to induce severe hypercholesterolemia and atherosclerosis progression. Plasma cholesterol was lowered by switching to chow diet and treatment with LDLR sense oligonucleotides to induce atherosclerosis regression. These mice received either empagliflozin or vehicle for three weeks. In the current study we make use of this model to study the effect of SGLT-2 inhibitor-mediated glucose lowering on atherosclerosis regression in a STZ-induced diabetes mouse model

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