Activation of calcineurin in human failing heart ventricle by endothelin-1, angiotensin II and urotensin II.
1 The calcineurin (CaN) enzyme-transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. 2 Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 M, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. 3 ET-1 increased contractile force in all 13 patients (P<0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P>0.1). FK506 had no effect on contractile force (P=0.12). 4 ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). 5 There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKC(epsilon) compared to samples incubated without PKC(epsilon). 6 Endogenous cardiostimulants which activate G(alpha)q-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate.
Li
Joan
J
Discipline of Medicine, University of Queensland, The Prince Charles Hospital, Chermside, QLD 4032, Australia.
Wang
Jianchun
J
Russell
Fraser D
FD
Molenaar
Peter
P
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014579:Urotensins / Q000494:pharmacology
D019332:Endothelin-1; D010455:Peptides; D010710:Phosphates; D014579:Urotensins; D000804:Angiotensin II; C029677:urotensin II; D011493:Protein Kinase C; D019703:Calcineurin; D016559:Tacrolimus