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.

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Cardiac ankyrin repeat protein (CARP) is a cardiac‐specific stress‐response protein which exerts diverse effects to modulate cardiac remodeling in response to pathological stimuli. We examined the role of CARP in postnatal cardiac development and function under basal conditions in mice. Transgenic mice that selectively overexpressed CARP in heart (CARP Tg) exhibited dilated cardiac chambers, impaired heart function, and cardiac fibrosis as assessed by echocardiography and histological staining. Furthermore, the mice had a shorter lifespan and reduced survival rate in response to ischemic acute myocardial infarction. Immunofluorescence demonstrated the overexpressed CARP protein was predominantly accumulated in the nuclei of cardiomyocytes. Microarray analysis revealed that the nuclear localization of CARP was associated with the suppression of calcium‐handling proteins. In vitro experiments revealed that CARP overexpression resulted in decreased cell contraction and calcium transient. In post‐mortem cardiac specimens from patients with dilated cardiomyopathy and end‐stage heart failure, CARP was significantly increased. Taken together, our data identified CARP as a crucial contributor in dilated cardiomyopathy and heart failure which was associated with its regulation of calcium‐handling proteins.

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