Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCepsilon in the heart, which are mitigated by endothelin receptor antagonist CPU0213.

AIM: Spatial dispersion of bioactive substances in the myocardium could serve as pathological basis for arrhythmogenesis and cardiac impairment by beta-adrenoceptor stimulation. We hypothesized that dispersed NADPH oxidase, protein kinase Cepsilon (PKCepsilon), early response gene (ERG), and matrix metalloproteinase 9(MMP-9) across the heart by isoproterenol (ISO) medication might be mediated by the endothelin (ET) - ROS pathway. We aimed to verify if ISO induced spatially heterogeneous distribution of pPKCepsilon, NAPDH oxidase, MMP-9 and ERG could be mitigated by either an ET receptor antagonist CPU0213 or iNOS inhibitor aminoguanidine.
METHODS: Rats were treated with ISO (1 mg/kg sc) for 10 days, and drug interventions (mg/kg) either CPU0213 (30 sc) or aminoguanidine (100 ip) were administered on days 8-10. Expression of NADPH oxidase, MMP-9, ERG, and PKCepsilon in the left and right ventricle (LV, RV) and septum (S) were measured separately.
RESULTS: Ventricular hypertrophy was found in the LV, S, and RV, in association with dispersed QTc and oxidative stress in ISO-treated rats. mRNA and protein expression of MMP-9, PKCepsilon, NADPH oxidase and ERG in the LV, S, and RV were obviously dispersed, with augmented expression mainly in the LV and S. Dispersed parameters were re-harmonized by either CPU0213, or aminoguanidine.
CONCLUSION: We found at the first time that ISO-induced dispersed distribution of pPKCepsilon, NADPH oxidase, MMP-9, and ERG in the LV, S, and RV of the heart, which were suppressed by either CPU0213 or aminoguanidine. It indicates that the ET-ROS pathway plays a role in the dispersed distribution of bioactive substances following sustained beta-receptor stimulation.