Targeting Sarcoplasmic Reticulum Calcium ATPase by Gene Therapy

Gwathmey, Judith K.; Yerevanian, Armen; Hajjar, Roger J.

doi:10.1089/hum.2013.2512

Cited by 25 publications

(28 citation statements)

References 100 publications

(89 reference statements)

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“…In contrast to the strong effect of LRP1 deficiency on SERCA2, LRP1 deficiency does not prevent the downregulatory effect of hypoxia on NCX-1 and CAV1.2. These results support a pivotal role of SERCA2 on the maintenance of calcium metabolism and are in agreement with the enormous potential of SERCA2 restoration by pharmacological action or gene delivery in the treatment of heart failure [37][38][39].…”

Section: Impact Of Lrp1 Deficiency On Calcium-handling Proteins and Csupporting

confidence: 87%

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Revuelta‐López¹,

Cal²,

Herraiz‐Martínez³

et al. 2015

Journal of Molecular and Cellular Cardiology

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Section: Impact Of Lrp1 Deficiency On Calcium-handling Proteins and Csupporting

confidence: 87%

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Revuelta‐López¹,

Cal²,

Herraiz‐Martínez³

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…Of the multiple regulators of calcium handling in heart failure, SERCA2 has received significant attention because of its primary role in calcium re-uptake to the sarcoplasmic reticulum. Indeed, SERCA2's activity is diminished in the failing heart 45 , and adenoviral administration of SERCA2a in failing cardiomyocytes improves contractility in various animal models of HF 46-49 . The resulting clinical trial, CUPID, demonstrated safety 50 and efficacy 51 of intracoronary infusion of recombinant AAV1/SERCA2a.…”

Section: Gene/molecular Therapymentioning

confidence: 99%

Recent Developments in Heart Failure

Dassanayaka

Jones

2015

Circulation Research

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Recent Developments in Cardiovascular Research:The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and effect of work performed in other fields. It is our hope and expectation that these "Recent Development" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research-The Editors.

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“…Under physiological conditions, this inhibition is relieved by either micromolar Ca 2+ or by phosphorylation of PLB, primarily by protein kinase A (PKA) at S16 [5]. Recent gene therapies targeting increased SERCA activity show promise for alleviation of heart failure [6]. Ablation of PLB or introduction of phosphomimetic mutant S16E-PLB suppress progression of heart failure in animal models [7,8,9].…”

Section: Introductionmentioning

confidence: 99%

Time-resolved FRET reveals the structural mechanism of SERCA–PLB regulation

Dong

Thomas

2014

Biochemical and Biophysical Research Communications

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We have used time-resolved fluorescence resonance energy transfer (TR-FRET) to characterize the interaction between phospholamban (PLB) and the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA) under conditions that relieve SERCA inhibition. Unphosphorylated PLB inhibits SERCA in cardiac SR, but inhibition is relieved by either micromolar Ca2+ or PLB phosphorylation. In both cases, it has been proposed that inhibition is relieved by dissociation of the complex. To test this hypothesis, we attached fluorophores to the cytoplasmic domains of SERCA and PLB, and reconstituted them functionally in lipid bilayers. TR-FRET, which permitted simultaneous measurement of SERCA-PLB binding and structure, was measured as a function of PLB phosphorylation and [Ca2+]. In all cases, two structural states of the SERCA-PLB complex were resolved, probably corresponding to the previously described T and R structural states of the PLB cytoplasmic domain. Phosphorylation of PLB at S16 completely relieved inhibition, partially dissociated the SERCA-PLB complex, and shifted the T/R equilibrium within the bound complex toward the R state. Since the PLB concentration in cardiac SR is at least 10 times that in our FRET measurements, we calculate that most of SERCA contains bound phosphorylated PLB in cardiac SR, even after complete phosphorylation. 4 μM Ca2+ completely relieved inhibition but did not induce a detectable change in SERCA-PLB binding or cytoplasmic domain structure, suggesting a mechanism involving structural changes in SERCA’s transmembrane domain. We conclude that Ca2+ and PLB phosphorylation relieve SERCA-PLB inhibition by distinct mechanisms, but both are achieved primarily by structural changes within the SERCA-PLB complex, not by dissociation of that complex.

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Targeting Sarcoplasmic Reticulum Calcium ATPase by Gene Therapy

Abstract: Although pharmacologic therapies have provided gains in reducing the mortality of heart failure,

Cited by 25 publications

References 100 publications

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Recent Developments in Heart Failure

Time-resolved FRET reveals the structural mechanism of SERCA–PLB regulation

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