Structural and functional implications of the phospholamban hinge domain: Impaired SR Ca2+ uptake as a primary cause of heart failure

Albrecht Schmidt, Jing Zhaia, Andrew Carr, Mike Gerst, John Lorenz, Piero Pollesello, Arto Annila, Brian Hoit, Evangelia Kranias (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

40 Citations (Scopus)

Abstract

Objective: The role of sarcoplasmic reticulum (SR) in the onset and progression of heart failure is controversial. We tested the hypothesis that impairment of SR Ca2+ sequestration may be a primary cause for progressive left ventricular (LV) dysfunction and the phospholamban hinge domain may be critical in this process.
Methods: A phospholamban hinge domain mutant (PLB/N27A) was introduced in the cardiac compartment of the phospholamban null mouse. An integrative approach was used to characterize the resulting cardiac phenotype at a structural, cellular, whole organ and intact animal level.
Results: NMR analysis revealed a defined alteration in the α-helical configuration between residues Q22 to F35 in mutant phospholamban. Transgenic lines expressing similar levels of mutant compared to wild-type phospholamban exhibited super-inhibition of the SR Ca2+ ATPase affinity for Ca2+ (EC50 0.52 μM) in oxalate-supported Ca2+ uptake measurements, which translated into impaired relaxation and attenuated responses to β-adrenergic stimulation. Importantly, a blunted force–frequency relation was observed in mutant hearts preceding left ventricular dilation. Upon aging to 10 months, the predominantly diastolic dysfunction progressed to congestive heart failure, characterized by induction of a fetal gene program, cardiac remodeling, lung congestion, depressed systolic function and early mortality.
Conclusion: Increased inhibition of Ca2+ sequestration may be a causative factor in the development of left ventricular dysfunction and myocyte remodeling leading to heart failure. Furthermore, the hinge domain may play an important role in transmitting PLB’s regulatory effects on SERCA.
Original languageEnglish
Pages (from-to)248-259
JournalCardiovascular Research
Volume56
Issue number2
DOIs
Publication statusPublished - 2002
MoE publication typeA1 Journal article-refereed

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Sarcoplasmic Reticulum
Heart Failure
Left Ventricular Dysfunction
Animal Structures
Oxalates
Calcium-Transporting ATPases
Adrenergic Agents
Muscle Cells
Dilatation
phospholamban
Phenotype
Lung
Mortality
Genes

Keywords

  • Ca-pump
  • calcium (cellular)
  • contractile function
  • heart failure
  • SR (function)

Cite this

Schmidt, Albrecht ; Zhaia, Jing ; Carr, Andrew ; Gerst, Mike ; Lorenz, John ; Pollesello, Piero ; Annila, Arto ; Hoit, Brian ; Kranias, Evangelia. / Structural and functional implications of the phospholamban hinge domain : Impaired SR Ca2+ uptake as a primary cause of heart failure. In: Cardiovascular Research. 2002 ; Vol. 56, No. 2. pp. 248-259.
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title = "Structural and functional implications of the phospholamban hinge domain: Impaired SR Ca2+ uptake as a primary cause of heart failure",
abstract = "Objective: The role of sarcoplasmic reticulum (SR) in the onset and progression of heart failure is controversial. We tested the hypothesis that impairment of SR Ca2+ sequestration may be a primary cause for progressive left ventricular (LV) dysfunction and the phospholamban hinge domain may be critical in this process. Methods: A phospholamban hinge domain mutant (PLB/N27A) was introduced in the cardiac compartment of the phospholamban null mouse. An integrative approach was used to characterize the resulting cardiac phenotype at a structural, cellular, whole organ and intact animal level. Results: NMR analysis revealed a defined alteration in the α-helical configuration between residues Q22 to F35 in mutant phospholamban. Transgenic lines expressing similar levels of mutant compared to wild-type phospholamban exhibited super-inhibition of the SR Ca2+ ATPase affinity for Ca2+ (EC50 0.52 μM) in oxalate-supported Ca2+ uptake measurements, which translated into impaired relaxation and attenuated responses to β-adrenergic stimulation. Importantly, a blunted force–frequency relation was observed in mutant hearts preceding left ventricular dilation. Upon aging to 10 months, the predominantly diastolic dysfunction progressed to congestive heart failure, characterized by induction of a fetal gene program, cardiac remodeling, lung congestion, depressed systolic function and early mortality. Conclusion: Increased inhibition of Ca2+ sequestration may be a causative factor in the development of left ventricular dysfunction and myocyte remodeling leading to heart failure. Furthermore, the hinge domain may play an important role in transmitting PLB’s regulatory effects on SERCA.",
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Schmidt, A, Zhaia, J, Carr, A, Gerst, M, Lorenz, J, Pollesello, P, Annila, A, Hoit, B & Kranias, E 2002, 'Structural and functional implications of the phospholamban hinge domain: Impaired SR Ca2+ uptake as a primary cause of heart failure', Cardiovascular Research, vol. 56, no. 2, pp. 248-259. https://doi.org/10.1016/S0008-6363(02)00541-2

Structural and functional implications of the phospholamban hinge domain : Impaired SR Ca2+ uptake as a primary cause of heart failure. / Schmidt, Albrecht; Zhaia, Jing; Carr, Andrew; Gerst, Mike; Lorenz, John; Pollesello, Piero; Annila, Arto; Hoit, Brian; Kranias, Evangelia (Corresponding Author).

In: Cardiovascular Research, Vol. 56, No. 2, 2002, p. 248-259.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Structural and functional implications of the phospholamban hinge domain

T2 - Impaired SR Ca2+ uptake as a primary cause of heart failure

AU - Schmidt, Albrecht

AU - Zhaia, Jing

AU - Carr, Andrew

AU - Gerst, Mike

AU - Lorenz, John

AU - Pollesello, Piero

AU - Annila, Arto

AU - Hoit, Brian

AU - Kranias, Evangelia

PY - 2002

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N2 - Objective: The role of sarcoplasmic reticulum (SR) in the onset and progression of heart failure is controversial. We tested the hypothesis that impairment of SR Ca2+ sequestration may be a primary cause for progressive left ventricular (LV) dysfunction and the phospholamban hinge domain may be critical in this process. Methods: A phospholamban hinge domain mutant (PLB/N27A) was introduced in the cardiac compartment of the phospholamban null mouse. An integrative approach was used to characterize the resulting cardiac phenotype at a structural, cellular, whole organ and intact animal level. Results: NMR analysis revealed a defined alteration in the α-helical configuration between residues Q22 to F35 in mutant phospholamban. Transgenic lines expressing similar levels of mutant compared to wild-type phospholamban exhibited super-inhibition of the SR Ca2+ ATPase affinity for Ca2+ (EC50 0.52 μM) in oxalate-supported Ca2+ uptake measurements, which translated into impaired relaxation and attenuated responses to β-adrenergic stimulation. Importantly, a blunted force–frequency relation was observed in mutant hearts preceding left ventricular dilation. Upon aging to 10 months, the predominantly diastolic dysfunction progressed to congestive heart failure, characterized by induction of a fetal gene program, cardiac remodeling, lung congestion, depressed systolic function and early mortality. Conclusion: Increased inhibition of Ca2+ sequestration may be a causative factor in the development of left ventricular dysfunction and myocyte remodeling leading to heart failure. Furthermore, the hinge domain may play an important role in transmitting PLB’s regulatory effects on SERCA.

AB - Objective: The role of sarcoplasmic reticulum (SR) in the onset and progression of heart failure is controversial. We tested the hypothesis that impairment of SR Ca2+ sequestration may be a primary cause for progressive left ventricular (LV) dysfunction and the phospholamban hinge domain may be critical in this process. Methods: A phospholamban hinge domain mutant (PLB/N27A) was introduced in the cardiac compartment of the phospholamban null mouse. An integrative approach was used to characterize the resulting cardiac phenotype at a structural, cellular, whole organ and intact animal level. Results: NMR analysis revealed a defined alteration in the α-helical configuration between residues Q22 to F35 in mutant phospholamban. Transgenic lines expressing similar levels of mutant compared to wild-type phospholamban exhibited super-inhibition of the SR Ca2+ ATPase affinity for Ca2+ (EC50 0.52 μM) in oxalate-supported Ca2+ uptake measurements, which translated into impaired relaxation and attenuated responses to β-adrenergic stimulation. Importantly, a blunted force–frequency relation was observed in mutant hearts preceding left ventricular dilation. Upon aging to 10 months, the predominantly diastolic dysfunction progressed to congestive heart failure, characterized by induction of a fetal gene program, cardiac remodeling, lung congestion, depressed systolic function and early mortality. Conclusion: Increased inhibition of Ca2+ sequestration may be a causative factor in the development of left ventricular dysfunction and myocyte remodeling leading to heart failure. Furthermore, the hinge domain may play an important role in transmitting PLB’s regulatory effects on SERCA.

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KW - calcium (cellular)

KW - contractile function

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KW - SR (function)

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DO - 10.1016/S0008-6363(02)00541-2

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