Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction

Abstract

Rationale: The renin-angiotensin system (RAS) is a complex regulatory network that maintains normal physiological functions. The role of the RAS in sepsis-induced myocardial dysfunction (SIMD) is poorly defined. Angiotensinogen (AGT) is the unique precursor of the RAS and gives rise to all angiotensin peptides. The effects and mechanisms of AGT in 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 (LPS) or cecal ligation and puncture (CLP) significantly enhanced AGT abundances in liver, heart, and plasma. Deficiency of hepatocyte-derived AGT (hepAGT), rather than cardiomyocyte-derived AGT (carAGT), alleviated septic cardiac dysfunction in mice and prolonged survival time. Further investigations revealed that the effects of hepAGT on SIMD were partially associated with augmented angiotensin II (AngII) production in circulation. In addition, hepAGT was internalized by LDL receptor-related protein 1 (LRP1) in cardiac fibroblasts (CF), and subsequently activated NLRP3 inflammasome via an AngII-independent pathway, ultimately promoting SIMD by suppressing Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) abundances in cardiomyocytes (CM). Conclusions: HepAGT promoted SIMD via both AngII-dependent and AngII-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.

The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

“…Elevated angiotensin II levels and imbalance with angiotensin-converting enzyme 2/Ang-(1-7)/Mas receptor in the liver induces hepatic ROS overproduction, lipid accumulation, and inflammation. A very recent study identified a liver-heart axis, showing that hepatocyte-derived, rather than locally synthesized, cardiac angiotensinogen, contributes to myocardial dysfunction in septic mouse models [11] . Compelling evidence from animal and human studies suggests that heightened activation of the SNS is a key contributor to the development of NAFLD [12] .…”

“…A very recent study identified a liver-heart axis, showing that hepatocyte-derived, rather than locally synthesized, cardiac angiotensinogen, contributes to myocardial dysfunction in septic mouse models. [11] Compelling evidence from animal and human studies suggests that heightened activation of the SNS is a key contributor to the development of NAFLD. [12] This lipolytic state, induced by sympathetic overactivity, results in increased levels of FFAs and triglycerides in the circulation and visceral deposition, which exacerbates NAFLD.…”

Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis

“…Whether all the other pressure load conditions also lead to increased ACE2 expression is unknown. On the other hand, we assume that due to changes in sample sources, mouse samples did not reveal substantial differences [ 78 ].…”

Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation

“…Investigation of molecules predicted to be critical up stream regulators strongly support proinflammatory signaling activation in the POLG RV. For instance, lipopolysaccharide, AGT (angiotensinogen), INFG were all predicted to be activated and clearly stimulate inflammation (e.g., [25][26][27]. Similarly, Zc3h12c, the top predicted inhibited upstream regulator, has been implicated as an inhibitor of NF-kB (28).…”