Deficiency Of Hepatocyte-derived Angiotensinogen Attenuates Sepsis-induced Myocardial Dysfunction

Background:Septic patients have multiple organ dysfunctions.Sepsis-induced myocardial dysfunction(SIMD),one of the common complications of sepsis,significantly increases the mortality of septic patients.SIMD has three main characteristics:(1)left ventricular dilatation with normal-or low-filling pressure,(2)reduced ventricular contractility,and(3)right ventricular dysfunction or left ventricular dysfunction with a reduced response to volume infusion.The renin-angiotensin system(RAS)is a complex regulatory network that maintains normal physiological functions.The role of the RAS in SIMD is poorly defined.Angiotensinogen(AGT)is a unique precursor of the RAS and gives rise to all angiotensin peptides.AGT can be used as an indicator of the status of the entire RAS.However,the effects and mechanisms of AGT in SIMD have not been defined.Our study determined the role of AGT in SIMD and investigate the underlying mechanisms.Methods & Results:Either intraperitoneal injection of lipopolysaccharide(LPS)or cecal ligation and puncture(CLP)induced myocardial dysfunction in mice.Western blotting revealed significantly enhanced AGT abundances in the liver and heart tissues of septic mice.Markedly elevated plasma AGT concentrations were found in septic mice by Enzyme-linked immunosorbent assay(ELISA).Deficiency of hepatocyte-derived AGT(hep AGT),rather than cardiomyocyte-derived AGT(car AGT),alleviated septic cardiac dysfunction in mice and prolonged survival time.Further investigations revealed that hep AGT exerted detrimental effects on SIMD partially due to augmented angiotensin II(Ang II)production in circulation.In addition,Immunoprecipitation(IP),ligand blotting,and lentivirus injection experiments suggested that hep AGT was internalized by LDL receptor-related protein 1(LRP1)in cardiac fibroblasts.Western blotting then confirmed that hep AGT activated NLRP3 inflammasome in cardiac fibroblasts via an Ang II-independent pathway.Furthermore,RNA-seq,Western blotting and cardiomyocyte calcium transient measurement verified that activated NLRP3 inflammasome in cardiac fibroblasts promoted SIMD by suppressing SERCA2 a abundances in cardiomyocytes.Conclusions:The current study indicated that hep AGT promoted SIMD via both classical Ang II-dependent and Ang II-independent pathways.Therefore,we identified a liver-heart axis by which AGT regulated development of SIMD.Our study may provide a potential novel therapeutic target for SIMD.