Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation.
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.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Lin-Lin
LL
Kang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Dong-Mei
DM
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Chun-Hua
CH
Ma
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Jian-Hua
JH
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Ke-Ke
KK
Jia
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Jia-Hui
JH
Liu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Rong
R
Wang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People's Republic of China.
Ling-Dong
LD
Kong
D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D018955:CD36 Antigens / Q000502:physiology*; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control*; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D009205:Myocarditis / Q000378:metabolism / Q000517:prevention & control*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D018955:CD36 Antigens; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000493:Allopurinol; D000171:Acrolein; C000605977:IRAK4 protein, rat; D017346:Protein Serine-Threonine Kinases; C012843:cinnamaldehyde