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

Xie Saiyang; Wu Qingqing; Xu Man; Liu Chen; Zhang Min; Xing Yun; Shi Wenke; Wu Haiming; Zeng Xiaofeng; Chen Si; Guo Haipeng; Deng Wei; Tang Qizhu

doi:10.1002/ctm2.266

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

Clin Transl Med. 2021 Jan;11(1):e266. doi: 10.1002/ctm2.266.

Authors

Xie Saiyang^{1

2}, Wu Qingqing^{1

2}, Xu Man^{1

2}, Liu Chen^{1

2}, Zhang Min^{1

2}, Xing Yun^{1

2}, Shi Wenke^{1

2}, Wu Haiming^{1

2}, Zeng Xiaofeng^{1

2}, Chen Si^{1

2}, Guo Haipeng^{3

4}, Deng Wei^{1

2

5}, Tang Qizhu^{1

2}

Affiliations

¹ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
² Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, People's Republic of China.
³ Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.
⁴ Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
⁵ Department of Cardiology, The Fifth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China.

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.

Keywords: Ca2+-handling; TLR7; cardiac dysfunction; septic cardiomyopathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiomyopathies / complications*
Cardiomyopathies / prevention & control*
Disease Models, Animal
Male
Membrane Glycoproteins / pharmacology*
Mice
Mice, Inbred C57BL
Sepsis / complications*
Systole
Toll-Like Receptor 7

Substances

Membrane Glycoproteins
Tlr7 protein, mouse
Toll-Like Receptor 7