Neprilysin Inhibitor-Angiotensin II Receptor Blocker Combination Therapy (Sacubitril/valsartan) Suppresses Atherosclerotic Plaque Formation and Inhibits Inflammation in Apolipoprotein E- Deficient Mice

Hui Zhang; Gangqiong Liu; Wenping Zhou; Wenjing Zhang; Kai Wang; Jinying Zhang

doi:10.1038/s41598-019-42994-1

Neprilysin Inhibitor-Angiotensin II Receptor Blocker Combination Therapy (Sacubitril/valsartan) Suppresses Atherosclerotic Plaque Formation and Inhibits Inflammation in Apolipoprotein E- Deficient Mice

Sci Rep. 2019 Apr 24;9(1):6509. doi: 10.1038/s41598-019-42994-1.

Authors

Hui Zhang¹, Gangqiong Liu¹, Wenping Zhou², Wenjing Zhang¹, Kai Wang¹, Jinying Zhang³

Affiliations

¹ Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.
² Department of Cardiology, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.
³ Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China. [email protected].

Abstract

We assessed the effects of the sacubitril/valsartan combination drug (LCZ696), in comparison to valsartan alone, on the progression of atherosclerotic plaque formation and inflammatory gene expression in apolipoprotein E- deficient mice (apoE^-/- mice). Seventy-two apoE^-/- mice were fed a western diet and a constrictive silastic tube was used to elicit carotid lesion formation. The animals were separated into a control group, a valsartan group or an LCZ696 group (n = 24 in each group). Plaques in the carotid artery were harvested 12 weeks later for histological examination. The levels of pro-inflammatory genes in the plasma and lesions were detected using real-time PCR and ELISA. Valsartan or LCZ696 treatment remarkably inhibited the expression of pro-inflammatory genes, including interleukin-6, matrix metalloproteinase-8 and monocyte chemotactic protein-1, in comparison with the control group. Meanwhile, both valsartan and LCZ696 suppressed the formation of atherosclerotic plaques by decreasing plaque lipid content and cross-sectional plaque area and increasing the content of plaque collagen and fibrous cap thickness. In particular, LCZ696 performed the best in suppressing atherosclerosis and inhibiting the level of pro-inflammatory genes. LCZ696 significantly ameliorated atherosclerosis and inflammation in apoE^-/- mice compared with valsartan.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminobutyrates / administration & dosage
Aminobutyrates / pharmacology*
Angiotensin II Type 1 Receptor Blockers / administration & dosage
Angiotensin II Type 1 Receptor Blockers / pharmacology*
Animals
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Biphenyl Compounds
Chemokine CCL2 / genetics
Chemokine CCL2 / metabolism
Drug Combinations
Drug Therapy, Combination
Gene Expression Regulation / drug effects
Inflammation / genetics
Inflammation / metabolism
Inflammation / prevention & control*
Interleukin-6 / genetics
Interleukin-6 / metabolism
Lipids / blood
Matrix Metalloproteinase 8 / genetics
Matrix Metalloproteinase 8 / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Neprilysin / antagonists & inhibitors*
Neprilysin / metabolism
Plaque, Atherosclerotic / drug therapy*
Plaque, Atherosclerotic / genetics
Plaque, Atherosclerotic / metabolism
RAW 264.7 Cells
Tetrazoles / administration & dosage
Tetrazoles / pharmacology*
Valsartan / administration & dosage
Valsartan / pharmacology*

Substances

Aminobutyrates
Angiotensin II Type 1 Receptor Blockers
Apolipoproteins E
Biphenyl Compounds
Ccl2 protein, mouse
Chemokine CCL2
Drug Combinations
Interleukin-6
Lipids
Tetrazoles
Valsartan
Neprilysin
Matrix Metalloproteinase 8
sacubitril and valsartan sodium hydrate drug combination