Excessive consumption of diets high in sugars and saturated fat, frequently known as western diet (WD), may lead to obesity and metabolic syndrome. Recent evidence shows that WD-induced obesity impairs cardiac function, but the underlying mechanisms are not fully understood. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of specific dietary nutrients, has emerged as a key contributor to cardiovascular disease pathogenesis. We tested the hypothesis that elevated circulating TMAO levels contribute to cardiac dysfunction in WD-induced obesity. CD1 mice were fed a normal diet (ND) or a WD, without or with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) in drinking water for 8 weeks. Compared with mice fed a ND, mice fed a WD showed a significant increase in body weight and dyslipidemia, and had markedly higher plasma TMAO levels at the end of the feeding protocol. Echocardiography revealed that cardiac systolic and diastolic function was impaired in mice fed a WD. DMB treatment had no effects on body weight and dyslipidemia, but significantly reduced plasma TMAO levels and prevented cardiac dysfunction in mice fed a WD. In addition, mice fed a WD had elevated expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin IL-1β, decreased expression of anti-inflammatory cytokine IL-10, and increased interstitial fibrosis in the hearts, all of which were prevented by DMB treatment. Notably, DMB treatment also reduced plasma TMAO levels in mice fed a ND but did not alter other parameters. These results suggest that consumption of a WD increases circulating TMAO levels, which lead to cardiac inflammation and fibrosis, contributing to cardiac dysfunction. Interventions that reduce circulating TMAO levels may be a novel therapeutic strategy for prevention and treatment of WD-induced cardiac dysfunction.

Serum levels of IL-6/8 are up-regulated in sepsis patients. Additionally, IL-6 has a greater sensitivity than IL-18. Serum IL-6 levels were positively correlated with the APACHE II score and heart rate, indicating that IL-6 could be used as a potential biomarker for sepsis.

The concept that flavonoids exert cardioprotection against myocardial ischemia-reperfusion (I/R) injury has been acknowledged by a large body of evidence. However, recent studies reported cardiotoxic effects of certain flavonoids, while the underlying mechanisms have remained largely elusive. Flavonoids have been demonstrated to activate aryl hydrocarbon receptor (Ahr), which is implicated in an array of cell signaling processes. The present study examined the cardioprotective roles of quercetin (Qu) and β-naphthoflavone (β-NF) against I/R injury and explored whether the underlying mechanism proceeds via molecular signaling downstream of Ahr. An oxygen glucose deprivation/reoxygenation (OGD/R) model of I/R was established in myocardial H9c2 cells in the absence or presence of Qu or β-NF. Qu as well as β-NF reversed OGD/R-induced overproduction of reactive oxygen species by increasing the anti-oxidative capacity of the cells and protected them from lethal injury, as demonstrated by a decreased cell death rate, lactate hydrogenase leakage and caspase-3 activity as determined by flow cytometry, colorimetric assay and western blot analysis, respectively. Immunocytochemistry, co-immunoprecipitation and western blot assays collectively revealed that Qu and β-NF engendered the translocation of Ahr from the cytoplasm into the cell nucleus, where binding of Ahr with the Ahr nuclear translocator (ARNT) blocked its binding to hypoxia-inducible factor (HIF)-1α, which inhibited the cardioprotection of HIF-1α, including the induction of nitric oxide (NO) and inhibition of vascular endothelial growth factor (VEGF) production. Ahr knockdown recovered the binding of ARNT to HIF-1α and the generation of NO and VEGF. The results of the present study suggested a dual character of Qu and β-NF in the process of myocardial I/R.