Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction

Jiabing Rong, Xinran Tao, Yao Lin, Haiqiong Zheng, Le Ning, Hong S. Lu, Alan Daugherty, Peng Shi, Adam E. Mullick, Sicong Chen, Zhaocai Zhang, Yinchuan Xu, Jian'An Wang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

RATIONALE: The renin-angiotensin system is a complex regulatory network that maintains normal physiological functions. The role of the renin-angiotensin system in sepsis-induced myocardial dysfunction (SIMD) is poorly defined. AGT (Angiotensinogen) is the unique precursor of the renin-angiotensin system and gives rise to all angiotensin peptides. The effects and mechanisms of AGT in the development of SIMD have not been defined. OBJECTIVE: To determine a role of AGT in SIMD and investigate the underlying mechanisms. METHODS AND RESULTS: Either intraperitoneal injection of lipopolysaccharide or cecal ligation and puncture significantly enhanced AGT abundances in liver, heart, and plasma. Deficiency of hepatocyte-derived AGT, rather than cardiomyocytederived AGT, alleviated septic cardiac dysfunction in mice and prolonged survival time. Further investigations revealed that the effects of hepatocyte-derived AGT on SIMD were partially associated with augmented Ang II (angiotensin II) production in circulation. In addition, hepatocyte-derived AGT was internalized by LRP1 (LDL [low-density lipoprotein] receptor-related protein 1) in cardiac fibroblasts and subsequently activated NLRP3 (NLR family pyrin domain-containing 3) inflammasome via an Ang II-independent pathway, ultimately promoting SIMD by suppressing SERCA2a (sarco[endo]plasmic reticulum Ca[2+]-ATPase 2a) abundances in cardiomyocytes. CONCLUSIONS: Hepatocyte-derived AGT promoted SIMD via both Ang II-dependent and Ang II-independent pathways. We identified a liver-heart axis by which AGT regulated development of SIMD. Our study may provide a potential novel therapeutic target for SIMD.

Original languageEnglish
Pages (from-to)547-564
Number of pages18
JournalCirculation Research
Volume129
Issue number5
DOIs
StatePublished - Aug 20 2021

Bibliographical note

Funding Information:
This work was supported by the National Key R&D Program of China (no. 2019YFA0110400 and no. 2016YFC1301204 to J. Wang), the National Natural Science Foundation of China (no. 81870292 to J. Wang, no. 81971860 to Y. Xu, no. 81772110 to Z. Zhang, no. 81801940 to Y. Zhou, and no. 81801330 to S. Chen), and the Key R&D projects of Zhejiang Province (no. 2015C03028 to J. Wang).

Publisher Copyright:
© 2021 American Heart Association, Inc.

Keywords

  • Angiotensin II
  • Angiotensinogen
  • Fibroblasts
  • Heart diseases
  • Sepsis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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