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Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias.

ABSTRACT: 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 (2Hz +/- 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.

SUBMITTER: Haghighi K

PROVIDER: S-EPMC4689614 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias.

Haghighi Kobra K Pritchard Tracy J TJ Liu Guan-Sheng GS Singh Vivek P VP Bidwell Philip P Lam Chi Keung CK Vafiadaki Elizabeth E Das Parthib P Ma Jianyong J Kunduri Swati S Sanoudou Despina D Florea Stela S Vanderbilt Erica E Wang Hong-Shang HS Rubinstein Jack J Hajjar Roger J RJ Kranias Evangelia G EG

Journal of molecular and cellular cardiology 20151009 Pt B

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, suggest ...[more]

PMID: 26455482

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Project description:BackgroundAcidemia, is associated with reduced cardiac function in animals, but no studies showing an effect of acidemia on cardiac function in humans are reported. In the present study, we examined the effect of acidemia on cardiac function assessed with transpulmonary thermodilution technique with integrated pulse contour analysis (Pulse Contour Cardiac Output, PiCCO™) in a large cohort of critically ill patients.MethodsThis was a prospective multicenter observational cross-sectional study of 297 patients from 6 intensive care units in London, England selected from all patients admitted consecutively between May 2018 and March 2019. Measurements of lowest plasma pH and concurrent assessment of cardiac function were obtained.FindingsThere was a significant difference between two pH categories (pH ≤ 7.28 vs. pH > 7.28) for the following variables of cardiac function: SVI (difference in means 32.7; 95% CI: 21 to 45 mL/m2; p < 0.001); GEF (18; 95% CI: 11 to 26%; p < 0.001), dPmax (-331; 95% CI: -510 to -153 mmHg/s; p = 0.001), CFI (0.7; 95% CI: 0.2 to 1.3 1/min; p = 0.01) and CPI (0.09; 95% CI: 0.03 to 0.15 W/m2; p < 0.001). However, there was no significant difference in CI (0.13; 95% CI: -0.20 to 0.47 L/min/m2; p = 0.12) between the pH categories. Also, a significant relationship was found between the quantitative pH and the following variables: SVI (132; 95% CI: 77 to 188 mL/m2; p < 0.001), GEF (74.7; 95% CI: 37.1 to 112.4%; p < 0.001), dPmax (-1587; 95% CI: -2361 to -815 mmHg/s; p < 0.001), CFI (3.5; 95% CI: 0.9 to 6.1 /min; p = 0.009), CPI (0.62; 95% CI: 0.36 to 0.88 W/m2; p < 0.001) and CI (regression coefficient 1.96; 95% CI:0.45 to 3.47 L/min/m2; p = 0.01).InterpretationAcidemia is associated with impaired cardiac function in seriously ill patients hospitalized in the intensive care unit supporting the potential value of early diagnosis and improvement of arterial pH in these patients.FundingThe study was partially supported by unrestricted funds from the UCLA School of Medicine.

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Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias.

Publications

Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias.

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