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

Kobra Haghighi, Tracy J. Pritchard, Guan Sheng Liu, Vivek P. Singh, Philip Bidwell, Chi Keung Lam, Elizabeth Vafiadaki, Parthib Das, Jianyong Ma, Swati Kunduri, Despina Sanoudou, Stela Florea, Erica Vanderbilt, Hong Shang Wang, Jack Rubinstein, Roger J. Hajjar, Evangelia G. Kranias

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)349-359
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume89
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

Fingerprint

Protein Phosphatase 1
Sarcoplasmic Reticulum
Cardiac Arrhythmias
Heart Failure
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Isoproterenol
Cardiac Myocytes
Phosphorylation
Ryanodine Receptor Calcium Release Channel
Ventricular Tachycardia
Transgenic Mice
Genes
Fibrosis
Animal Models
phospholamban
Therapeutics

Keywords

  • Calcium cycling
  • Cardiac function
  • Heart failure
  • Inhibitor-1
  • Protein phosphatase 1

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Haghighi, K., Pritchard, T. J., Liu, G. S., Singh, V. P., Bidwell, P., Lam, C. K., ... Kranias, E. G. (2015). Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias. Journal of Molecular and Cellular Cardiology, 89, 349-359. https://doi.org/10.1016/j.yjmcc.2015.10.004

Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias. / Haghighi, Kobra; Pritchard, Tracy J.; Liu, Guan Sheng; Singh, Vivek P.; Bidwell, Philip; Lam, Chi Keung; Vafiadaki, Elizabeth; Das, Parthib; Ma, Jianyong; Kunduri, Swati; Sanoudou, Despina; Florea, Stela; Vanderbilt, Erica; Wang, Hong Shang; Rubinstein, Jack; Hajjar, Roger J.; Kranias, Evangelia G.

In: Journal of Molecular and Cellular Cardiology, Vol. 89, 01.12.2015, p. 349-359.

Research output: Contribution to journalArticle

Haghighi, K, Pritchard, TJ, Liu, GS, Singh, VP, Bidwell, P, Lam, CK, Vafiadaki, E, Das, P, Ma, J, Kunduri, S, Sanoudou, D, Florea, S, Vanderbilt, E, Wang, HS, Rubinstein, J, Hajjar, RJ & Kranias, EG 2015, 'Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias', Journal of Molecular and Cellular Cardiology, vol. 89, pp. 349-359. https://doi.org/10.1016/j.yjmcc.2015.10.004
Haghighi, Kobra ; Pritchard, Tracy J. ; Liu, Guan Sheng ; Singh, Vivek P. ; Bidwell, Philip ; Lam, Chi Keung ; Vafiadaki, Elizabeth ; Das, Parthib ; Ma, Jianyong ; Kunduri, Swati ; Sanoudou, Despina ; Florea, Stela ; Vanderbilt, Erica ; Wang, Hong Shang ; Rubinstein, Jack ; Hajjar, Roger J. ; Kranias, Evangelia G. / Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 89. pp. 349-359.
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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 (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.",
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AU - Pritchard, Tracy J.

AU - Liu, Guan Sheng

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AU - Bidwell, Philip

AU - Lam, Chi Keung

AU - Vafiadaki, Elizabeth

AU - Das, Parthib

AU - Ma, Jianyong

AU - Kunduri, Swati

AU - Sanoudou, Despina

AU - Florea, Stela

AU - Vanderbilt, Erica

AU - Wang, Hong Shang

AU - Rubinstein, Jack

AU - Hajjar, Roger J.

AU - Kranias, Evangelia G.

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