Interplay of Liver–Heart Inflammatory Axis and Cannabinoid 2 Receptor Signaling in an Experimental Model of Hepatic Cardiomyopathy

Abstract

Background and Aims Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)–induced liver fibrosis, by monitoring echocardiography and intracardiac pressure–volume relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid‐2 receptor (CB2‐R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation and fibrosis on cardiac function. Approach and Results BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines, and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic, and macrovascular functions; cardiac inflammation (increased macrophage inflammatory protein 1, interleukin‐1, P‐selectin, cluster of differentiation 45–positive cells); and oxidative stress (increased malondialdehyde, 3‐nitrotyrosine, and nicotinamide adenine dinucleotide phosphate oxidases). CB2‐R up‐regulation was observed in both livers and hearts of mice exposed to BDL. CB2‐R activation markedly improved hepatic inflammation, impaired microcirculation, and fibrosis. CB2‐R activation also decreased serum tumor necrosis factor‐alpha levels and improved cardiac dysfunction, myocardial inflammation, and oxidative stress, underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy. Conclusions We propose BDL‐induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similar to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension and impaired macrovascular and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver–heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g., with selective CB2‐R agonists) may delay or prevent the development of cardiomyopathy in severe liver disease.

Hepatocardiac or Cardiohepatic Interaction: From Traditional Chinese Medicine to Western Medicine

“…Bile duct ligation (BDL)-induced advanced liver fibrosis is a suitable mouse model to investigate the pathophysiology of hepatic/cirrhotic cardiomyopathy at a preclinical level, as it resembles the characteristics of the clinical syndrome seen in patients [55]. One of the main contributors to the BDL-induced liver fibrosis is tissue inflammation, which contributes, as liver failure develops, to the production and excretion of several inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), into the blood, culminating in a general inflammatory response and subsequent oxidative stress, and the heart is one of the major organs involved [55,56]. Cannabinoid-2 receptor (CB 2 -R), a negative regulator of ischemia/reperfusion (I/R)-induced liver injury and carbon tetrachlorideinduced hepatic fibrosis, is upregulated in the liver and heart of BDL mice [55,[57][58][59].…”

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

“…The mechanism of CBD in the latter studies is complex and probably results from direct antioxidant properties [3,29] but may also be related to an effect on the endocannabinoid system, which is important for the modulation of oxidative stress [30,31]. CB 1 receptors are mainly associated with its promotion [32][33][34], whereas CB 2 [35][36][37][38][39] and GPR18 [40,41] receptors reduce oxidation parameters in cardiovascular system including heart. There are contradictory reports regarding modulation of oxidative stress by TRPV1 and GPR55 receptors [30,31].…”

Organ-organ communication: The liver's perspective

“…The liver-heart inflammatory axis has a pivotal pathological role in the development of hepatic cardiomyopathy. Cannabinoid-2 receptor activation markedly improved hepatic/myocardial inflammation, decreased serum TNF-α level, and cardiac dysfunction, underlining the importance of inflammatory mediators in the pathology of this disease 113 . Hepatocyte-specific knockout of IL-6 was sufficient to block aging-induced cardiac arrhythmia in a fruit fly model 114 .…”