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

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Abstract

Calcium ion (Ca2+) cycle plays a crucial role in the contraction and relaxation of cardiomyocytes. The sarcoplasmic reticulum (SR) acts as an organelle for storing Ca2+, which mediated the release and re-uptake of Ca2+ during contraction and relaxation. Disorders of SR function lead to the dysfunction of Ca2+ cycle and myocardial cell function. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) acts as a subtype of SERCA expressed in the heart, which mediates the contraction of cardiomyocytes and Ca2+ in the cytoplasm to re-enter into the SR. The rate of uptake of Ca2+ by the SR determines the rate of myocardial relaxation. The regulation of SERCA2a activity controls the contractility and relaxation of the heart, affecting cardiac function. The expression and activity of SERCA2a are reduced in failing hearts. Gene therapy by increasing the expression of SERCA2a in the heart has been proven effective. In addition, SERCA2a is regulated by a variety of factors, including transmembrane micropeptides, protein kinases, and post-translational modifications (PTMs). In this review, we discuss the regulatory factors of SERCA2a and provide new insights into future treatments and the direction of heart failure research. In addition, gene therapy for SERCA2a has recently emerged as therapeutic option and hence will be discussed in this review.

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Abbreviations

AAV1:

adeno-associated vector type 1

ALN:

another-regulin

Ca2+ :

calcium ion

CaMKII:

calcium/calmodulin-dependent protein kinase II

DWORF:

dwarf open reading frame

ELN:

endoregulin

HF:

heart failure

KATs:

lysine acetyltransferases

KDACs:

lysine deacetylase

LTCC:

L-type Ca2+ channel

MLN:

myoregulin

NATs:

N-acetyltransferases

PLB:

phospholamban

PKA:

cAMP-dependent protein kinase

PP1:

protein phosphatase 1

PTM:

post-translational modification

RyR2:

ryanodine receptor 2

SERCA2a:

sarco/endoplasmic reticulum Ca2+ ATPase 2a

SLN:

sarcolipin

SPEG:

striated muscle–specific protein kinase

SR:

sarcoplasmic reticulum

SUMO:

small ubiquitin-like modifier

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Funding

This study is supported by grants from the Tianjin Outstanding Youth Science Foundation (17JCJQJC46200), the National Natural Science Foundation of China (NSFC 81774050), the Natural Science Foundation of Tianjin (17JCYBJC29000), and the Ministry of Education of People’s Republic of China “Program for Innovative Research Team in University” (No. IRT_16R54).

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Authors and Affiliations

  1. Tianjin Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Number 314 Anshanxi Road, Nankai District, Tianjin, 300193, People’s Republic of China

    Liu Zhihao, Ni Jingyu, Li Lan, Sarhene Michael, Guo Rui & Fan Guanwei

  2. State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China

    Liu Zhihao, Ni Jingyu, Li Lan, Sarhene Michael, Guo Rui & Fan Guanwei

  3. Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin, 300450, People’s Republic of China

    Bian Xiyun & Liu Xiaozhi

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  1. Liu Zhihao
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  2. Ni Jingyu
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Correspondence to Fan Guanwei.

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Zhihao, L., Jingyu, N., Lan, L. et al. SERCA2a: a key protein in the Ca2+ cycle of the heart failure. Heart Fail Rev 25, 523–535 (2020). https://doi.org/10.1007/s10741-019-09873-3

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