Fig. 4
Schematic representation of the role of iNOS and eNOS in DOX-induced cardiomyopathy. iNOS is mainly distributed in macrophages and is not expressed under physiological conditions. The iNOS is activated under stress, converts L-arginine to L-citrulline and generates a large amount of NO with the help of the co-factors FAD, FMN, BH4, heme complex-ferriprotoporphyrin IX. NO can react with O2·− to generate ONOO−, which inhibits GPX and exacerbates oxidative stress. The eNOS is mainly distributed in endothelial cells and formed in its physiological state can reduce O2 to NO. In the stress state, eNOS is uncoupled to reduce O2 to O2·−, aggravating the oxidative stress. Drugs including phenylalanine-butyramide(P), fisetin(Fis), curcumin(Cur), crocin(Cro), eicosapentaenoic acid(E) can attenuate oxidative stress by downregulating the activation of iNOS. Drugs including nebivolol(N), fenofibrate(Fen), ursolic acid(UA), folic acid(FA), fluvastatin(Flu) attenuate oxidative stress by downregulating the activation of eNOS. iNOS: inducible nitric oxide synthase, eNOS: endothelial nitric oxide synthase, BH4: tetrahydrobiopterin, FAD: flavin adenine dinucleotide, FMN: flavin mononucleotide, CaM: calmodulin. (By Figdraw.)