Abstract
Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury, and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis. Scavenger receptor CD36, Toll-like receptor 4 (TLR4), TLR6, IL-1R-associated kinase 4/1 (IRAK4/1), nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, interleukin-1β, transforming growth factor-β (TGF-β), drosophila mothers against DPP homolog (Smad) 2/3 phosphorylation and Smad4 were increased in animal and H9c2 cell models. These pathological processes were further evaluated in ox-LDL or fructose-exposed H9c2 cells pretreated with ROS scavenger and CD36 specific inhibitor, or IRAK1/4 inhibitor, and transfected with CD36, NLRP3, or IRAK4/1 siRNA, demonstrating that NLPR3 inflammasome activation through CD36-mediated TLR4/6-IRAK4/1 signaling may promote cardiac inflammation and fibrosis. Cinnamaldehyde and allopurinol reduced cardiac oxidative stress to suppress NLPR3 inflammasome activation and TGF-β/Smads signaling by inhibiting CD36-mediated TLR4/6-IRAK4/1 signaling under fructose induction. These results suggest that the blockage of CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation by cinnamaldehyde and allopurinol may protect against fructose-induced cardiac inflammation and fibrosis.
Highlights
Between CD36 and ox-Low density lipoprotein (LDL) induces the secretion of inflammatory cytokine interleukin (IL)-1β9–11, which is mediated by assembly of the activation of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome[12]
20, 40 and 80 mg/kg cinnamaldehyde was found to attenuate fructose-induced these changes in rats in a dose-dependent manner, except 20 mg/kg cinnamaldehyde had no effect on body weight (Table 1), systolic blood pressure (SBP) (Table 1) and oxidized LDL (ox-LDL) (Table 2)
This study for the first time demonstrated that fructose induction increased cardiac oxidative stress and reactive oxygen species (ROS) to up-regulate CD36, and subsequently provoked NLRP3 inflammasome in a TLR4/6-IRAK4/1-dependent manner, promoting cardiac inflammation and fibrosis in metabolic syndrome of rats with high serum ox-LDL levels
Summary
Between CD36 and ox-LDL induces the secretion of inflammatory cytokine interleukin (IL)-1β9–11, which is mediated by assembly of the activation of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome[12]. Cinnamaldehyde decreases serum levels of total triglyceride (TG) and total cholesterol (TC) in mice and patients with diabetes[31,32] It reduces ROS production and IL-1βsecretion to alleviate metabolic disturbance-associated inflammation in murine RAW 264.7 or J774A.1 macrophages, suppresses plasma TLR4 expression and inflammatory cell infiltrate in myocardium from viral myocarditis mice[33,34,35]. We hypothesized that cinnamaldehyde and allopurinol may reduce oxidative stress to inhibit NLRP3 imflammasome activation via CD36-meidated TLR4/6-IRAK4/1-dependent manner in the pathogenesis of fructose-induced cardiac injury. We constructed fructose feeding-induced rat model with high serum ox-LDL level, cardiac oxidative stress, inflammation and fibrosis in metabolic syndrome, and evaluated protective effects of cinnamaldehyde and allopurinol in this animal model. This study suggests that cinnamaldehyde and allopurinol may protect against fructose-induced cardiac inflammation and fibrosis associated with metabolic syndrome
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