Τίτλος:
Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
A hallmark of human and experimental heart failure is deficient sarcoplasmic reticulum (SR) Ca-uptake reflecting impaired contractile function. This is at least partially attributed to dephosphorylation of phospholamban by increased protein phosphatase 1 (PP1) activity. Indeed inhibition of PP1 by transgenic overexpression or gene-transfer of constitutively active inhibitor-1 improved Ca-cycling, preserved function and decreased fibrosis in small and large animal models of heart failure, suggesting that inhibitor-1 may represent a potential therapeutic target. We recently identified a novel human polymorphism (G109E) in the inhibitor-1 gene with a frequency of 7% in either normal or heart failure patients. Transgenic mice, harboring cardiac-specific expression of G109E inhibitor-1, exhibited decreases in contractility, Ca-kinetics and SR Ca-load. These depressive effects were relieved by isoproterenol stimulation. Furthermore, stress conditions (2 Hz +/- Iso) induced increases in Ca-sparks, Ca-waves (60% of G109E versus 20% in wild types) and after-contractions (76% of G109E versus 23% of wild types) in mutant cardiomyocytes. Similar findings were obtained by acute expression of the G109E variant in adult cardiomyocytes in the absence or presence of endogenous inhibitor-1. The underlying mechanisms included reduced binding of mutant inhibitor-1 to PP1, increased PP1 activity, and dephosphorylation of phospholamban at Ser16 and Thr17. However, phosphorylation of the ryanodine receptor at Ser2808 was not altered while phosphorylation at Ser2814 was increased, consistent with increased activation of Ca/calmodulin-dependent protein kinase II (CaMKII), promoting aberrant SR Ca-release. Parallel in vivo studies revealed that mutant mice developed ventricular ectopy and complex ventricular arrhythmias (including bigeminy, trigeminy and ventricular tachycardia), when challenged with isoproterenol. Inhibition of CaMKII activity by KN-93 prevented the increased propensity to arrhythmias. These findings suggest that the human G109E inhibitor-1 variant impairs SR Ca-cycling and promotes arrhythmogenesis under stress conditions, which may present an additional insult in the compromised function of heart failure carriers. © 2015 Elsevier Ltd.
Συγγραφείς:
Haghighi, K.
Pritchard, T.J.
Liu, G.-S.
Singh, V.P.
Bidwell, P.
Lam, C.K.
Vafiadaki, E.
Das, P.
Ma, J.
Kunduri, S.
Sanoudou, D.
Florea, S.
Vanderbilt, E.
Wang, H.-S.
Rubinstein, J.
Hajjar, R.J.
Kranias, E.G.
Περιοδικό:
Journal of Molecular and Cellular Cardiology
Εκδότης:
INSTAP Academic Press
Λέξεις-κλειδιά:
calcium; calcium calmodulin dependent protein kinase II; cell protein; G109E inhibitor 1 protein; glutamic acid; glycine; isoprenaline; phospholamban; phosphoprotein phosphatase 1; protein variant; ryanodine receptor; serine; threonine; unclassified drug; calcium binding protein; catecholamine; isoprenaline; phosphoprotein phosphatase inhibitor 1; protein; sodium calcium exchange protein, adult; animal cell; animal experiment; animal model; animal tissue; arrhythmogenesis; Article; calcium cell level; calcium mobilization; calcium signaling; calcium transport; cell mutant; controlled study; DNA polymorphism; ectopia cordis; enzyme activation; enzyme activity; enzyme inhibition; G109E inhibitor 1 gene; gene frequency; heart failure; heart muscle cell; heart muscle contractility; heart stress; heart ventricle arrhythmia; heart ventricle bigeminy; heart ventricle tachycardia; heart ventricle trigeminy; human; major clinical study; male; mouse; nonhuman; pathophysiology; priority journal; protein binding; protein dephosphorylation; protein expression; protein function; protein phosphorylation; smooth endoplasmic reticulum; transgenic mouse; animal; cardiac muscle cell; diastole; drug effects; genetics; heart; heart arrhythmia; heart contraction; kinetics; metabolism; phosphorylation; rat; sarcoplasmic reticulum; single nucleotide polymorphism, Animals; Arrhythmias, Cardiac; Calcium; Calcium Signaling; Calcium-Binding Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Catecholamines; Diastole; Heart; Humans; Isoproterenol; Kinetics; Mice, Transgenic; Myocardial Contraction; Myocytes, Cardiac; Phosphorylation; Polymorphism, Single Nucleotide; Proteins; Rats; Sarcoplasmic Reticulum; Sodium-Calcium Exchanger
DOI:
10.1016/j.yjmcc.2015.10.004
