title: Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Drum
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biology, Seattle University, 901 12th Ave., Seattle, WA 98122, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Luckey
authors.affiliation: Department of Pharmacology, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Merle L
authors.initials: ML
authors.lastname: Gilbert
authors.affiliation: Department of Pharmacology, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: G Stanley
authors.initials: GS
authors.lastname: McKnight
authors.affiliation: Department of Pharmacology, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.|Howard Hughes Medical Institute, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.affiliation: Deparment of Physiology & Membrane Biology, University of California, One Shields Ave., Davis, CA 95616, USA.
authors.forename: L Fernando
authors.initials: LF
authors.lastname: Santana
authors.affiliation: Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA; qcliu@u.washington.edu.
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D054758:A Kinase Anchor Proteins / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000150:complications; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016276:Ventricular Function; D020257:Ventricular Remodeling; D000099211:Phospholamban
chemical_list: D054758:A Kinase Anchor Proteins; D019703:Calcineurin; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D050778:NFATC Transcription Factors; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C520665:Akap5 protein, mouse; C000592748:ryanodine receptor 2. mouse; C506947:Atp2a2 protein, mouse
keywords: AKAP150; Cardiac hypertrophy ; Contractility ; Heart failure ; Pathological remodelling 