The antioxidant edaravone attenuates ER-stress-mediated cardiac apoptosis and dysfunction in rats with autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) is mediated by myocardial infiltration by myosin-specific T-cells secreting inflammatory cytokines. In this study, rat models of EAM were prepared by injection with porcine cardiac myosin. One week after immunization, edaravone was administered intraperitoneally at 3 or 10 mg/kg/day to rats for 2 weeks. Cardiac function was measured by haemodynamic and echocardiographic studies and TUNEL assay was performed. Left ventricular (LV) expression of NADPH oxidase sub-units (p47(phox) and p67(phox)), pro-inflammatory cytokines (TNF-alpha), endoplasmic reticulum (ER) stress signalling proteins (GRP78, caspase-12 and GADD153) and mitogen-activated protein kinase (MAPK) family proteins (phospho-p38 MAPK and phospho-JNK) were measured by western blotting. Edaravone improved LV function in a dose-dependent manner. Central venous pressure was significantly low and LV ejection fraction and fractional shortening was significantly high in edaravone groups compared with those in the vehicle group. In addition, edaravone treatment down-regulated LV expressions of p47(phox), TNF-alpha, GADD153, phospho-p38 MAPK and phospho-JNK. Furthermore, the LV expressions of p67(phox), GRP78, caspase-12 and TUNEL-positive cells of rats with EAM treated with edaravone were significantly low compared with those of the vehicle group. These findings suggest that edaravone ameliorated the progression of EAM by inhibiting oxidative and ER stress and, subsequently, cardiac apoptosis.
Shimazaki
Hiroko
H
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan.
Watanabe
Kenichi
K
Veeraveedu
Punniyakoti T
PT
Harima
Meilei
M
Thandavarayan
Rajarajan A
RA
Arozal
Wawaimuli
W
Tachikawa
Hitoshi
H
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D000077553:Edaravone; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D008297:Male; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000517:prevention & control
D000975:Antioxidants; D000077553:Edaravone; D000983:Antipyrine