Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve

Lei Li, Jing Li, Benjamin M. Drum, Yi Chen, Haifeng Yin, Xiaoyun Guo, Stephen W. Luckey, Merle L. Gilbert, G. Stanley McKnight, John D. Scott, Luis Fernando Santana, Qinghang Liu

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Aims Impaired Ca2+cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca2+cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signalling complexes in the pathogenesis of heart failure has not been investigated. Methods and results Here we examined how AKAP150 signalling complexes impact Ca2+cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodelling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not affect calcineurin-nuclear factor of activated T cells signalling in cardiomyocytes or pressure overload-or agonist-induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca2+regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca2+cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. Conclusions These findings define a critical role for AKAP150 in regulating Ca2+cycling and myocardial ionotropy following pathological stress, suggesting the AKAP150 signalling pathway may serve as a novel therapeutic target for heart failure.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalCardiovascular Research
Volume113
Issue number2
DOIs
StatePublished - 2017

Fingerprint

Heart Failure
Calcium
Muscle Cells
Pressure
Cardiac Myocytes
Adrenergic Agents
NFATC Transcription Factors
Ryanodine Receptor Calcium Release Channel
Calcineurin
Dilated Cardiomyopathy
Cardiomegaly
Sarcoplasmic Reticulum
Immunoprecipitation
Knockout Mice
Protein Kinases
Fibrosis
Hemodynamics
Myocardial Infarction
Proteins
Therapeutics

Keywords

  • AKAP150
  • Cardiac hypertrophy
  • Contractility
  • Heart failure
  • Pathological remodelling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve. / Li, Lei; Li, Jing; Drum, Benjamin M.; Chen, Yi; Yin, Haifeng; Guo, Xiaoyun; Luckey, Stephen W.; Gilbert, Merle L.; Stanley McKnight, G.; Scott, John D.; Santana, Luis Fernando; Liu, Qinghang.

In: Cardiovascular Research, Vol. 113, No. 2, 2017, p. 147-159.

Research output: Contribution to journalArticle

Li, L, Li, J, Drum, BM, Chen, Y, Yin, H, Guo, X, Luckey, SW, Gilbert, ML, Stanley McKnight, G, Scott, JD, Santana, LF & Liu, Q 2017, 'Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve', Cardiovascular Research, vol. 113, no. 2, pp. 147-159. https://doi.org/10.1093/cvr/cvw221
Li, Lei ; Li, Jing ; Drum, Benjamin M. ; Chen, Yi ; Yin, Haifeng ; Guo, Xiaoyun ; Luckey, Stephen W. ; Gilbert, Merle L. ; Stanley McKnight, G. ; Scott, John D. ; Santana, Luis Fernando ; Liu, Qinghang. / Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve. In: Cardiovascular Research. 2017 ; Vol. 113, No. 2. pp. 147-159.
@article{43243003028543feb15b70dea32b3a7c,
title = "Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve",
abstract = "Aims Impaired Ca2+cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca2+cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signalling complexes in the pathogenesis of heart failure has not been investigated. Methods and results Here we examined how AKAP150 signalling complexes impact Ca2+cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodelling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not affect calcineurin-nuclear factor of activated T cells signalling in cardiomyocytes or pressure overload-or agonist-induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca2+regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca2+cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. Conclusions These findings define a critical role for AKAP150 in regulating Ca2+cycling and myocardial ionotropy following pathological stress, suggesting the AKAP150 signalling pathway may serve as a novel therapeutic target for heart failure.",
keywords = "AKAP150, Cardiac hypertrophy, Contractility, Heart failure, Pathological remodelling",
author = "Lei Li and Jing Li and Drum, {Benjamin M.} and Yi Chen and Haifeng Yin and Xiaoyun Guo and Luckey, {Stephen W.} and Gilbert, {Merle L.} and {Stanley McKnight}, G. and Scott, {John D.} and Santana, {Luis Fernando} and Qinghang Liu",
year = "2017",
doi = "10.1093/cvr/cvw221",
language = "English (US)",
volume = "113",
pages = "147--159",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve

AU - Li, Lei

AU - Li, Jing

AU - Drum, Benjamin M.

AU - Chen, Yi

AU - Yin, Haifeng

AU - Guo, Xiaoyun

AU - Luckey, Stephen W.

AU - Gilbert, Merle L.

AU - Stanley McKnight, G.

AU - Scott, John D.

AU - Santana, Luis Fernando

AU - Liu, Qinghang

PY - 2017

Y1 - 2017

N2 - Aims Impaired Ca2+cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca2+cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signalling complexes in the pathogenesis of heart failure has not been investigated. Methods and results Here we examined how AKAP150 signalling complexes impact Ca2+cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodelling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not affect calcineurin-nuclear factor of activated T cells signalling in cardiomyocytes or pressure overload-or agonist-induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca2+regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca2+cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. Conclusions These findings define a critical role for AKAP150 in regulating Ca2+cycling and myocardial ionotropy following pathological stress, suggesting the AKAP150 signalling pathway may serve as a novel therapeutic target for heart failure.

AB - Aims Impaired Ca2+cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca2+cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signalling complexes in the pathogenesis of heart failure has not been investigated. Methods and results Here we examined how AKAP150 signalling complexes impact Ca2+cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodelling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not affect calcineurin-nuclear factor of activated T cells signalling in cardiomyocytes or pressure overload-or agonist-induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca2+regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca2+cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. Conclusions These findings define a critical role for AKAP150 in regulating Ca2+cycling and myocardial ionotropy following pathological stress, suggesting the AKAP150 signalling pathway may serve as a novel therapeutic target for heart failure.

KW - AKAP150

KW - Cardiac hypertrophy

KW - Contractility

KW - Heart failure

KW - Pathological remodelling

UR - http://www.scopus.com/inward/record.url?scp=85015236014&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015236014&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvw221

DO - 10.1093/cvr/cvw221

M3 - Article

C2 - 27856611

AN - SCOPUS:85015236014

VL - 113

SP - 147

EP - 159

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

ER -