iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation

[Display omitted] •Combination of HDF and L-NAME induced cardiac mitochondrial dysfunction and HFpEF phenotype.•Both long-term and short-term iNOS inhibition mitigated mitochondrial dysfunction and oxidative stress in HFpEF heart.•Akt S-nitrosylation was involved into the development of HFpEF.•Both...

Full description

Saved in:
Bibliographic Details
Published in:Journal of advanced research Vol. 43; pp. 175 - 186
Main Authors: Guo, Yongzheng, Wen, Junjie, He, An, Qu, Can, Peng, Yuce, Luo, Suxin, Wang, Xiaowen
Format: Journal Article
Language:English
Published: Egypt Elsevier B.V 01.01.2023
Elsevier
Subjects:
Akt S-nitrosylation
Animals
Heart Failure - metabolism
HFpEF
iNOS
Mice
Mitochondria - metabolism
Mitochondria - pathology
Mitochondrial function
Nitric Oxide Synthase Type II - metabolism
Original
Oxidative Stress
Proto-Oncogene Proteins c-akt - metabolism
Stroke Volume - physiology
Akt S-nitrosylation
iNOS
HFpEF
Mitochondrial function
ISSN:2090-1232, 2090-1224, 2090-1224
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] •Combination of HDF and L-NAME induced cardiac mitochondrial dysfunction and HFpEF phenotype.•Both long-term and short-term iNOS inhibition mitigated mitochondrial dysfunction and oxidative stress in HFpEF heart.•Akt S-nitrosylation was involved into the development of HFpEF.•Both long-term and short-term iNOS inhibition reduced Akt S-nitrosylation and rescued HFpEF phenotype. Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, the pathophysiological basis of HFpEF remains poorly understood. The aim of the present study was to investigate the role of inducible nitric oxide synthase (iNOS) and its underlying mechanism in a high-fat diet and Nω-nitro-L-arginine methyl ester-induced HFpEF mouse model. The selective iNOS inhibitor L-NIL was used to examine the effects of short-term iNOS inhibition, whereas the long-term effects of iNOS deficiency were evaluated using iNOS-null mice. Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation were then measured. The results demonstrated that both pharmacological inhibition and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress and Akt S-nitrosylation, leading to an ameliorated HFpEF phenotype in mice. In vitro, iNOS directly induced Akt S-nitrosylation at cysteine 224 residues , leading to oxidative stress, while inhibiting insulin-mediated glucose uptake in myocytes. Altogether, the present findings suggested an important role for iNOS in the pathophysiological development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2090-1232
2090-1224
2090-1224
DOI:10.1016/j.jare.2022.03.003