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ID 119293
Title Alternative
Effects of LCZ696 on Diabetes-Induced Endothelial Dysfunction
Author
Munkhjargal, Uugantsetseg Tokushima University
Fukuda, Daiju Osaka Metropolitan University KAKEN Search Researchers
Maeda, Juri Tokushima University
Okamoto, Shintaro Tokushima University
Bavuu, Oyunbileg Tokushima University|Osaka Metropolitan University
Yamamoto, Takayuki Tokushima University|Osaka Metropolitan University
Keywords
Diabetes
Sacubitril/valsartan
Natriuretic peptide
Endothelial dysfunction
Content Type
Journal Article
Description
Aims: LCZ696 (sacubitril/valsartan) exerts cardioprotective effects. Recent studies have suggested that it improves the endothelial function; however, the underlying mechanisms have not been thoroughly investigated. We investigated whether LCZ696 ameliorates diabetes-induced endothelial dysfunction.
Methods: Diabetes was induced using streptozotocin in 8-week-old male C57BL/6 mice. Diabetic mice were randomly assigned to receive LCZ696 (100 mg/kg/day), valsartan (50 mg/kg/day), or a vehicle for three weeks. The endothelium-dependent and endothelium-independent vascular responses of the aortic segments were determined based on the response to acetylcholine and sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVEC) and aortic segments obtained from C57BL/6 mice were used to perform in vitro and ex vivo experiments, respectively.
Results: LCZ696 and valsartan reduced the blood pressure in diabetic mice (P<0.05). The administration of LCZ696 (P<0.001) and valsartan (P<0.01) ameliorated endothelium-dependent vascular relaxation, but not endothelium-independent vascular relaxation, under diabetic conditions. LCZ696, but not valsartan, increased eNOSSer1177 (P=0.06) and Akt (P<0.05) phosphorylation in the aorta. In HUVEC, methylglyoxal (MGO), a major precursor of advanced glycation end products, decreased eNOSSer1177 phosphorylation (P<0.05) and increased eNOSThr495 phosphorylation (P<0.001). However, atrial natriuretic peptide (ANP) reversed these effects. ANP also ameliorated the MGO-induced impairment of endothelium-dependent vascular relaxation in the aortic segments (P<0.05), although L-NAME completely blocked this effect (P<0.001).
Conclusion: LCZ696 ameliorated diabetes-induced endothelial dysfunction by increasing the bioavailability of ANP. Our findings suggest that LCZ696 has a vascular protective effect in a diabetic model and highlight that it may be more effective than valsartan.
Journal Title
Journal of Atherosclerosis and Thrombosis
ISSN
18803873
13403478
Publisher
Japan Atherosclerosis Society
Volume
31
Issue
9
Start Page
1333
End Page
1340
Published Date
2024
Rights
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc-sa/4.0/).
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DOI (Published Version)
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language
eng
TextVersion
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departments
Medical Sciences
University Hospital