SERCA2a: a key protein in the Ca2+ cycle of the heart failure

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“…5A-B). (21). In support of this hypothesis, DWORF enhances SERCA2a activity and contractility in a HF mouse model (22).…”

Section: Dworf Activates Serca2a In the Absence Of Plbmentioning

confidence: 66%

The transmembrane peptide DWORF activates SERCA2a via dual mechanisms

Yuen

Stroik

et al. 2021

Journal of Biological Chemistry

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“…The causes of HF are complex, but growing evidence indicates that central factors include increased basal cytosolic [Ca 2+ ], correlated with decreased [Ca 2+ ] in the SR lumen. Since SERCA2a is the major determinant of cytosolic [Ca 2+ ], increasing SERCA2a activity is a potential therapy for a myriad of chronic cardiac pathologies (20). In support of this hypothesis, DWORF enhances SERCA2a activity and contractility in a HF mouse model (21).…”

Section: Discussionmentioning

confidence: 91%

The transmembrane domain of DWORF activates SERCA directly; P15 and W22 residues are essential

Stroik

Yuen

et al. 2020

Preprint

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The Ca-ATPase isoform 2a (SERCA2a) re-sequesters cytosolic Ca2+ into the sarcoplasmic reticulum (SR) of cardiac myocytes, enabling muscle relaxation during diastole. A central factor in heart failure is abnormally high cytosolic [Ca2+], resulting in pathophysiology and decreased cardiac performance. Therefore, augmentation of the SERCA2a Ca2+ transport activity is a promising therapeutic approach. A novel transmembrane peptide, dwarf open reading frame (DWORF), is proposed to enhance SR Ca2+ uptake and myocyte contractility by displacing the protein phospholamban (PLB) from its inhibitory site on SERCA2a. In the present study, we have developed several cell-based FRET biosensor systems for time-resolved FRET (TR-FRET) measurements of the protein-protein interactions and structural changes in SERCA2a complexes with PLB and/or DWORF. To test the hypothesis that DWORF competes with PLB to occupy the putative SERCA2a binding site, we transiently transfected DWORF into a stable cell line expressing SERCA2a labeled with green fluorescent protein (GFP, the FRET donor) and PLB labeled with red fluorescent protein (RFP, the FRET acceptor). We observed a significant decrease in FRET efficiency, consistent with a decrease in the fraction of SERCA2a bound to PLB. Functional analysis demonstrates that DWORF activates SERCA in both the presence and absence of PLB. Furthermore, using site-directed mutagenesis, we generated DWORF variants that do not activate SERCA, thus identifying residues that are necessary for functional SERCA2a-DWORF interactions. This work advances our mechanistic understanding of the regulation of SERCA2a by small transmembrane proteins and sets the stage for future therapeutic development in heart failure research.

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“…In addition, there are two other DETXs detected in VCP TG mice that were related to ATP synthesis and hydrolysis in mitochondria and are responsible for the energy metabolism in the stressed heart, including Atp5j , which is required for F1 and Fo interactions [ 60 ], and Atp2a2 , a gene that encodes one of the SERCA Ca(2+)-ATPases. Atp2a2 catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen [ 61 , 62 ], and is involved in calcium sequestration associated with muscular excitation and contraction [ 63 ]. These data indicate a new mechanism that VCP enhances cell survival by regulating these variants of mitochondrial genes which provide a new research interest in future research.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization reveals novel mechanisms underlying the valosin-containing protein-mediated cardiac protection against heart failure

Zhou

Chen

et al. 2020

Redox Biology

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Chronic hypertension is a key risk factor for heart failure. However, the underlying molecular mechanisms are not fully understood. Our previous studies found that the valosin-containing protein (VCP), an ATPase-associated protein, was significantly decreased in the hypertensive heart tissues. In this study, we tested the hypothesis that restoration of VCP protected the heart against pressure overload-induced heart failure. With a cardiac-specific transgenic (TG) mouse model, we showed that a moderate increase of VCP was able to attenuate chronic pressure overload-induced maladaptive cardiac hypertrophy and dysfunction. RNA sequencing and a comprehensive bioinformatic analysis further demonstrated that overexpression of VCP in the heart normalized the pressure overload-stimulated hypertrophic signals and repressed the stress-induced inflammatory response. In addition, VCP overexpression promoted cell survival by enhancing the mitochondria resistance to the oxidative stress via activating the Rictor-mediated-gene networks. VCP was also found to be involved in the regulation of the alternative splicing and differential isoform expression for some genes that are related to ATP production and protein synthesis by interacting with long no-coding RNAs and histone deacetylases, indicating a novel epigenetic regulation of VCP in integrating coding and noncoding genomic network in the stressed heart. In summary, our study demonstrated that the rescuing of a deficient VCP in the heart could prevent pressure overload-induced heart failure by rectifying cardiac hypertrophic and inflammatory signaling and enhancing the cardiac resistance to oxidative stress, which brought in novel insights into the understanding of the mechanism of VCP in protecting patients from hypertensive heart failure.

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SERCA2a: a key protein in the Ca2+ cycle of the heart failure

Cited by 97 publications

References 85 publications

The transmembrane peptide DWORF activates SERCA2a via dual mechanisms

The transmembrane peptide DWORF activates SERCA2a via dual mechanisms

The transmembrane domain of DWORF activates SERCA directly; P15 and W22 residues are essential

Genomic characterization reveals novel mechanisms underlying the valosin-containing protein-mediated cardiac protection against heart failure

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