Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation

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.

Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats

“…Numerous approaches for inhibition of ischemic cardiac fibrosis have been described 20, 21, 22. However, very little is known about the role of AMPK in cardiac fibrosis induced by left coronary artery ligation as yet.…”

Differential role of the NLRP3 inflammasome in infection and tumorigenesis

“…This suggests that MCC950 could have a potential therapeutic effect in patients with NLRP3‐associated inflammatory or autoimmune diseases . Cinnamaldehyde and allopurinol, which possess antioxidative and anti‐inflammatory activities, relieve cardiac inflammation and fibrosis in fructose‐induced cardiac injury related to NLRP3 inflammasome activation . The widely used antidiabetic drug metformin and the sirtuin 1 activator resveratrol prevent endoplasmic reticulum stress‐associated NLRP3 inflammasome activation in adipose tissue of diabetic mice .…”

Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling

“…In addition, MCC950 effectively ameliorates the pathological responses to experimental autoimmune encephalomyelitis and improves the survival rate in a mouse model of CAPS, suggesting a potential therapeutic effect for NLRP3‐associated inflammatory and autoimmune diseases 61 . Cinnamaldehyde and allopurinol, which possess antioxidative and anti‐inflammatory activities, were beneficial in relieving cardiac inflammation and fibrosis in fructose‐induced cardiac injury related to NLRP3 inflammasome activation 62 . In addition, the widely used antidiabetic drug metformin and the sirtuin 1 activator resveratrol were preventive the NLRP3 inflammasome activation in adipose tissue dysfunction models 63 .…”