Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling

Ujihara, Yoshihiro; Iwasaki, Keiichiro; Takatsu, Satomi; Hashimoto, Ken; Naruse, Keiji; Mohri, Satoshi; Katanosaka, Yuki

doi:10.1093/cvr/cvw113

Cited by 24 publications

(32 citation statements)

References 45 publications

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“…The latter antibody was raised against a synthetic peptide corresponding to residues 102–114 of mouse Fam64a (CQSGTKWLMETQV). Samples were then labeled with fluorochrome-conjugated secondary antibodies (Thermo-Fisher) as described 25, 26 . When necessary, DAPI staining for DNA or phalloidin staining for F-actin filaments was also performed.…”

Section: Methodsmentioning

confidence: 99%

Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice

Hashimoto

Kodama

Honda

et al. 2017

Sci Rep

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Fetal cardiomyocytes actively proliferate to form the primitive heart in utero in mammals, but they stop dividing shortly after birth. The identification of essential molecules maintaining this active cardiomyocyte proliferation is indispensable for potential adult heart regeneration. A recent study has shown that this proliferation depends on a low fetal oxygen condition before the onset of breathing at birth. We have established an isolation protocol for mouse fetal cardiomyocytes, performed under strict low oxygen conditions to mimic the intrauterine environment, that gives the highest proliferative activities thus far reported. Oxygen exposure during isolation/culture markedly inhibited cell division and repressed cell cycle-promoting genes, and subsequent genome-wide analysis identified Fam64a as a novel regulatory molecule. Fam64a was abundantly expressed in hypoxic fetal cardiomyocyte nuclei, but this expression was drastically repressed by oxygen exposure, and in postnatal cardiomyocytes following the onset of breathing and the resulting elevation of oxygen tension. Fam64a knockdown inhibited and its overexpression enhanced cardiomyocyte proliferation. Expression of a non-degradable Fam64a mutant suggested that optimum Fam64a expression and subsequent degradation by anaphase-promoting complex/cyclosome (APC/C) during the metaphase-to-anaphase transition are required for fetal cardiomyocyte division. We propose that Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice.

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Section: Methodsmentioning

confidence: 99%

Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice

Hashimoto

Kodama

Honda

et al. 2017

Sci Rep

Self Cite

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“…To control expression level of NCX1 in cardiomyocytes, we used transgenic mice in which NCX1 expression was controlled by a cardiac-specific, DOX-dependent promoter, as previously described [1]. We crossed two lines of transgenic mice: one carrying the canine NCX1 gene under the control of the minimal cytomegalovirus promoter, and the other carrying a gene encoding the reverse tetracycline transactivator (rtTA) protein under the control of an α-myosin heavy chain promoter.…”

Section: Animalsmentioning

confidence: 99%

“…JP2 is a membrane-binding protein that physically connects the T-tubule membrane and SR membrane [5]. We and others have reported that T-tubule disorganization is associated with a significant decrease in JP2 expression [1,6,7]. In addition, JP2…”

Section: Introductionmentioning

confidence: 96%

“…However, the importance of NCX1 in the development of heart failure (HF) is unclear. Recently, we demonstrated that induced NCX1 overexpression attenuates pressure-overload-induced pathological cardiac remodeling [1].…”

Section: Introductionmentioning

confidence: 99%

“…T-tubule disorganization is tightly linked to impaired Ca 2+ handling and contractility and represents a common pathological alternation in failing myocytes [2][3][4]. Interestingly, induced NCX1 overexpression also prevents T-tubule disorganization in pressure-overloaded hearts [1]. However, the role of NCX1 in the maintenance of T-tubule structure has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Effects of induced Na+/Ca2+ exchanger overexpression on the spatial distribution of L-type Ca2+ channels and junctophilin-2 in pressure-overloaded hearts

Ujihara

Mohri

Katanosaka

2016

Biochemical and Biophysical Research Communications

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The Na/Ca exchanger 1 (NCX1) is an essential Ca efflux system in cardiomyocytes. Although NCX1 is distributed throughout the sarcolemma, a subpopulation of NCX1 is localized to transverse (T)-tubules. There is growing evidence that T-tubule disorganization is a causal event that shifts the transition from hypertrophy to heart failure (HF). However, the detailed molecular mechanisms have not been clarified. Previously, we showed that induced NCX1 expression in pressure-overloaded hearts attenuates defective excitation-contraction coupling and HF progression. Here, we examined the effects of induced NCX1 overexpression on the spatial distribution of L-type Ca channels (LTCCs) and junctophilin-2 (JP2), a structural protein that connects the T-tubule and sarcoplasmic reticulum membrane, in pressure-overloaded hearts. Quantitative analysis showed that the regularity of NCX1 localization was significantly decreased at 8 weeks after transverse aortic constriction (TAC)-surgery; however, T-tubule organization and the regularities of LTCC and JP2 immunofluorescent signals were maintained at this time point. These observations demonstrated that release of NCX1 from the T-tubule area occurred before the onset of T-tubule disorganization and LTCC and JP2 mislocalization. Moreover, induced NCX1 overexpression at 8 weeks post-TAC not only recovered NCX1 regularity but also prevented the decrease in LTCC and JP2 regularities at 16 weeks post-TAC. These results suggested that NCX1 may play an important role in the proper spatial distribution of LTCC and JP2 in T-tubules in the context of pressure-overloading.

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Overexpression of Na+-HCO3– cotransporter contributes to the exacerbation of cardiac remodeling in mice with myocardial infarction by increasing intracellular calcium overload

Chen

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling

Abstract: Induced overexpression of NCX1 attenuated pressure overload-induced pathological cardiac remodelling. Thus, maintaining NCX1 activity may be a potential therapeutic strategy for preventing the progression of HF.

Cited by 24 publications

References 45 publications

Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice

Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice

Effects of induced Na+/Ca2+ exchanger overexpression on the spatial distribution of L-type Ca2+ channels and junctophilin-2 in pressure-overloaded hearts

Overexpression of Na+-HCO3– cotransporter contributes to the exacerbation of cardiac remodeling in mice with myocardial infarction by increasing intracellular calcium overload

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