Abstract
In the present study, we used lipopolysaccharide- (LPS-) stimulated H9C2 cardiomyocytes to investigate whether irisin treatment attenuates septic cardiomyopathy via Fundc1-related mitophagy. Fundc1 levels and mitophagy were significantly reduced in LPS-stimulated H9C2 cardiomyocytes but were significantly increased by irisin treatment. Irisin significantly increased ATP production and the activities of mitochondrial complexes I and III in the LPS-stimulated cardiomyocytes. Irisin also improved glucose metabolism and significantly reduced LPS-induced levels of reactive oxygen species by increasing the activities of antioxidant enzymes, glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH). TUNEL assays showed that irisin significantly reduced LPS-stimulated cardiomyocyte apoptosis by suppressing the activation of caspase-3 and caspase-9. However, the beneficial effects of irisin on oxidative stress, mitochondrial metabolism, and viability of LPS-stimulated H9C2 cardiomyocytes were abolished by silencing Fundc1. These results demonstrate that irisin abrogates mitochondrial dysfunction, oxidative stress, and apoptosis through Fundc1-related mitophagy in LPS-stimulated H9C2 cardiomyocytes. This suggests irisin is a potentially useful treatment for septic cardiomyopathy, though further investigations are necessary to confirm our findings.
Highlights
Sepsis refers to excessive activation of the immune system in response to microbial infections that result in inflammationrelated injury [1, 2]
We investigated if irisin treatment protects against sepsis-induced cardiomyopathy via Fundc1related mitophagy using LPS-stimulated H9C2 cardiomyocytes as a model
These results demonstrated that Fundc1-related mitophagy was activated by irisin in LPS-stimulated cardiomyocytes
Summary
Sepsis refers to excessive activation of the immune system in response to microbial infections that result in inflammationrelated injury [1, 2]. Sepsis-induced myocardial injury is termed as septic cardiomyopathy, which is associated with increased morbidity and mortality. The pathogenesis of septic cardiomyopathy includes oxidative stress, calcium imbalance, mitochondrial dysfunction, endoplasmic reticulum stress, autophagy inhibition, activation of programmed cell death activation, and immune disorder [5, 6]. We demonstrated that cardiac dysfunction during LPS-induced sepsis involved mitochondrial fission-associated mitochondrial damage. Excessive mitochondrial fission promotes mitochondrial damage, reduced synthesis of mitochondrial ATP, and cardiomyocyte death via mitochondria-dependent apoptotic pathway, which results in reduced cardiac performance [7, 8]. Mitochondrial dysfunction is a potential molecular mechanism underlying septic cardiomyopathy [9, 10]
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