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


CONCLUSIONS
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.
Cheng
Yu-si
YS
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Dai
De-zai
DZ
Dai
Yin
Y
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D005786:Gene Expression Regulation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006984:Hypertrophy / Q000139:chemically induced; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C513821:CPU0213; D002316:Cardiotonic Agents; D065128:Endothelin Receptor Antagonists; D006146:Guanidines; D011720:Pyrazoles; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D051744:Protein Kinase C-epsilon; D020780:Matrix Metalloproteinase 9; D007545:Isoproterenol; C004479:pimagedine