β₃-Adrenergic receptor blockade reduces mortality in endotoxin-induced heart failure by suppressing induced nitric oxide synthase and saving cardiac metabolism

Abstract

The β₃-adrenergic receptor (β₃AR) is related to myocardial fatty acid metabolism and its expression has been implicated in heart failure. In this study, we investigated the role of β₃AR in sepsis-related myocardial dysfunction using lipopolysaccharide (LPS)-induced endotoxemia as a model of cardiac dysfunction. We placed mice into three treatment groups and treated each with intraperitoneal injections of the β₃AR agonist CL316243 (CL group), the β₃AR antagonist SR59230A (SR group), or normal saline (NS group). Survival rates were significantly improved in the SR group compared with the other treatment groups. Echocardiography analyses revealed cardiac dysfunction within 6-12 h of LPS injections, but the outcome was significantly better for the SR group. Myocardial ATP was preserved in the SR group but was decreased in the CL-treated mice. Additionally, quantitative PCR analysis revealed that expression levels of genes associated with fatty acid oxidation and glucose metabolism were significantly higher in the SR group. Furthermore, the expression levels of mitochondrial membrane protein complexes were preserved in the SR group. Electron microscope studies showed significant accumulation of lipid droplets in the CL group. Moreover, inducible nitric oxide synthase (iNOS) protein expression and nitric oxide were significantly reduced in the SR group. The in vitro study demonstrated that β₃AR has an independent iNOS pathway that does not go through the nuclear factor-κB pathway. These results suggest that blockading β₃AR improves impaired energy metabolism in myocardial tissues by suppressing iNOS expression and recovers cardiac function in animals with endotoxin-induced heart failure.<b>NEW & NOTEWORTHY</b> Nitric oxide production through stimulation of β₃-adrenergic receptor (β₃AR) may improve cardiac function in cases of chronic heart failure. We demonstrated that the blockade of β₃AR improved mortality and cardiac function in endotoxin-induced heart failure. We also determined that LPS-induced inducible nitric oxide synthase has a pathway that is independent of nuclear factor-κB, which worsened cardiac metabolism and mortality in the acute phase of sepsis. Treatment with the β₃AR antagonist had a favorable effect. Thus, the blockade of β₃AR could offer a novel treatment for sepsis-related heart failure.