title: Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis.
abstract: We hypothesized that modulation of endothelin-converting enzyme-1 (ECE-1) activity would affect phosphorylation of p38-mitogen activated protein kinase (p38-MAPK) and potentiate apoptosis in adult rat ventricular myocytes (ARVMs) during sepsis. The activity of ECE-1 in ARVMs was altered by increasing the substrate availability for ECE-1 by exogenous administration of bigendothelin-1 (bigET-1, 100 nM) and by inhibiting ECE-1 using FR901533 (10 microM) for 24-h. FR901533 significantly decreased the concentration of ET-1 in both sham and sepsis groups. FR901533 decreased p38-MAPK phosphorylation in sepsis but not in sham group. BigET-1 upregulated p38-MAPK phosphorylation, produced hypertrophy, decreased cell viability and reversed FR901533-induced down-regulation of p38-MAPK phosphorylation in both groups. Although, FR901533 did not affect cell cross-sectional area, it significantly reduced the viability of ARVM in both groups. The peak shortening of sham ARVMs was elevated by bigET-1, FR901533 and pretreatment with FR901533 followed by bigET-1. However, the contractility of septic ARVMs was not altered by either bigET-1 or FR901533 treatments per se. Septic ARVM exhibited significantly increased caspase-3 activity at 12 and 24-h. Pretreatment with FR901533 significantly elevated caspase-3 activity in both sham and sepsis group. The data demonstrated that bigET-1-induced hypertrophy in septic ARVM correlates with an ECE-1 dependent-activation of p38-MAPK. The results suggest that non-responsiveness of ARVM to bigET-1 is due to ECE-1 dependent apoptosis. We concluded that ECE-1 may play a crucial role in ARVM dysfunction via increased caspase-3 activity and p38-MAPK phosphorylation during sepsis.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, 208 Sudro Hall, Fargo, ND 58105, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Aberle
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Avadhesh C
authors.initials: AC
authors.lastname: Sharma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000473:pathology* / Q000503:physiopathology*; D013754:Tetracyclines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D013754:Tetracyclines; C088494:WS 79089B; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes