Role of endothelin in the induction of cardiac hypertrophy in vitro.
Endothelin (ET-1) is a peptide hormone mediating a wide variety of biological processes and is associated with development of cardiac dysfunction. Generally, ET-1 is regarded as a molecular marker released only in correlation with the observation of a hypertrophic response or in conjunction with other hypertrophic stress. Although the cardiac hypertrophic effect of ET-1 is demonstrated, inotropic properties of cardiac muscle during chronic ET-1-induced hypertrophy remain largely unclear. Through the use of a novel in vitro multicellular culture system, changes in contractile force and kinetics of rabbit cardiac trabeculae in response to 1 nM ET-1 for 24 hours can be observed. Compared to the initial force at t = 0 hours, ET-1 treated muscles showed a ~2.5 fold increase in developed force after 24 hours without any effect on time to peak contraction or time to 90% relaxation. ET-1 increased muscle diameter by 12.5 ± 3.2% from the initial size, due to increased cell width compared to non-ET-1 treated muscles. Using specific signaling antagonists, inhibition of NCX, CaMKII, MAPKK, and IP3 could attenuate the effect of ET-1 on increased developed force. However, among these inhibitions only IP3 receptor blocker could not prevent the increase muscle size by ET-1. Interestingly, though calcineurin-NFAT inhibition could not suppress the effect of ET-1 on force development, it did prevent muscle hypertrophy. These findings suggest that ET-1 provokes both inotropic and hypertrophic activations on myocardium in which both activations share the same signaling pathway through MAPK and CaMKII in associated with NCX activity.
Department of Physiology and Cell Biology and D Davis Heart Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
Tepmanas
T
Bupha-Intr
Kaylan M
KM
Haizlip
Paul M L
PM
Janssen
D000704:Analysis of Variance; D000818:Animals; D001596:Benzylamines; D001896:Boron Compounds; D019703:Calcineurin / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology*; D016572:Cyclosporine; D016232:Endothelins / Q000494:pharmacology*; D015151:Immunoblotting; D066298:In Vitro Techniques; D007211:Indoles; D007700:Kinetics; D008301:Maleimides; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides; D013890:Thiourea / Q000031:analogs & derivatives; D013997:Time Factors; D000096926:Benzenesulfonamides
D001596:Benzylamines; D001896:Boron Compounds; D019703:Calcineurin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D016572:Cyclosporine; D016232:Endothelins; D007211:Indoles; D008301:Maleimides; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D013449:Sulfonamides; D013890:Thiourea; C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C072105:KN 93; D000096926:Benzenesulfonamides; C109986:2-aminoethoxydiphenyl borate; C070515:bisindolylmaleimide I