Key result
Pharmacological inhibition of iNOS and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress, and Akt S-nitrosylation, ameliorating the HFpEF phenotype in mice.
Why the study?
Heart failure with preserved ejection fraction causes high morbidity and mortality with no effective therapies, and its pathophysiological basis remains poorly understood.
Does iNOS inhibition improve cardiac and mitochondrial function in a mouse model of HFpEF?
Does iNOS inhibition improve cardiac and mitochondrial function in a mouse model of HFpEF?
Inhibition of iNOS ameliorates the HFpEF phenotype in mice by mitigating mitochondrial dysfunction and Akt S-nitrosylation, suggesting a potential therapeutic target.
Hypothesis-generating for iNOS inhibition in HFpEF; leaves open translation from mice to patients.
INTRODUCTION: 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. OBJECTIVE: -nitro-L-arginine methyl ester-induced HFpEF mouse model. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Guo et al. (2022) studied Heart failure with preserved ejection fraction (HFpEF). iNOS inhibition (L-NIL) and iNOS deficiency was evaluated on Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation. Pharmacological inhibition of iNOS and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress, and Akt S-nitrosylation, ameliorating the HFpEF phenotype in mice.
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