Dataset Information

Activation of Toll-like receptor 7 provides cardioprotection in septic cardiomyopathy-induced systolic dysfunction.

ABSTRACT:

Background

As a pattern recognition receptor, Toll-like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy.

Methods

We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7-knockout (TLR7^-/- ), wild-type (WT) mice, cardiac-specific TLR7-transgenic (cTG-TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad-TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca²⁺ imaging, western blotting, immunostaining, and quantitative real-time polymerase chain reaction (qPCR).

Results

We found that TLR7 knockout markedly exacerbated sepsis-induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7^-/- mice displayed weaker Ca²⁺ handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS-induced systolic dysfunction, and loxoribine (TLR7-specific agonist) improved LPS-induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)-protein kinase A (PKA) pathway, which upregulated phosphorylate-phospholamban (p-PLN) (Ser16) and promoted sarco/endoplasmic reticulum Ca²⁺ ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca²⁺ handling in response to sepsis. While improved Ca²⁺ handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG-TLR7 mice. Consistently, TLR7 overexpression improved LPS-induced Ca²⁺ -handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype.

Conclusions

Our data demonstrated that activation of TLR7 protected against sepsis-induced cardiac dysfunction through promoting cAMP-PKA-PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis.

SUBMITTER: Saiyang X

PROVIDER: S-EPMC7775988 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Activation of Toll-like receptor 7 provides cardioprotection in septic cardiomyopathy-induced systolic dysfunction.

Saiyang Xie X Qingqing Wu W Man Xu X Chen Liu L Min Zhang Z Yun Xing X Wenke Shi S Haiming Wu W Xiaofeng Zeng Z Si Chen C Haipeng Guo G Wei Deng D Qizhu Tang T

Clinical and translational medicine 20210101 1

<h4>Background</h4>As a pattern recognition receptor, Toll-like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy.<h4>Methods</h4>We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7-knockou ...[more]

PMID: 33463061

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Project description:Mitochondrial dysfunction is a key contributor to septic cardiomyopathy. Although recent literature implicates dynamin related protein 1 (Drp1) and its mitochondrial adaptor fission 1 (Fis1) in the development of pathologic fission and mitochondrial failure in neurodegenerative disease, little is known about the role of Drp1/Fis1 interaction in the context of sepsis-induced cardiomyopathy. Our study tests the hypothesis that Drp1/Fis1 interaction is a major driver of sepsis-mediated pathologic fission, leading to mitochondrial dysfunction in the heart.MethodsH9C2 cardiomyocytes were treated with lipopolysaccharide (LPS) to evaluate changes in mitochondrial membrane potential, oxidative stress, cellular respiration, and mitochondrial morphology. Balb/c mice were treated with LPS, cardiac function was measured by echocardiogaphy, and mitochondrial morphology determined by electron microscopy (EM). Drp1/Fis1 interaction was inhibited by P110 to determine whether limiting mitochondrial fission can reduce LPS-induced oxidative stress and cardiac dysfunction.ResultsLPS-treated H9C2 cardiomyocytes demonstrated a decrease in mitochondrial respiration followed by an increase in mitochondrial oxidative stress and a reduction in membrane potential. Inhibition of Drp1/Fis1 interaction with P110 attenuated LPS-mediated cellular oxidative stress and preserved membrane potential. In vivo, cardiac dysfunction in LPS-treated mice was associated with increased mitochondrial fragmentation. Treatment with P110 reduced cardiac mitochondrial fragmentation, prevented decline in cardiac function, and reduced mortality.ConclusionsSepsis decreases cardiac mitochondrial respiration and membrane potential while increasing oxidative stress and inducing pathologic fission. Treatment with P110 was protective in both in vitro and in vivo models of septic cardiomyopathy, suggesting a key role of Drp1/Fis1 interaction, and a potential target to reduce its morbidity and mortality.

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Dataset Information

Activation of Toll-like receptor 7 provides cardioprotection in septic cardiomyopathy-induced systolic dysfunction.

Background

Methods

Results

Conclusions

Publications

Activation of Toll-like receptor 7 provides cardioprotection in septic cardiomyopathy-induced systolic dysfunction.

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