Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Aims Although increased Na+/Ca2+ exchanger 1 (NCX1) expression is observed during heart failure (HF), the pathological role of NCX1 during the progression of HF remains unclear. We examined alterations of NCX1 expression and activity in hearts after transverse aortic constriction (TAC) surgery and explored whether NCX1 influences pressure overload-induced pathological cardiac remodelling. Methods and results We generated novel transgenic mice in which NCX1 expression is controlled by a cardiac-specific, doxycycline (DOX)-dependent promoter. In the absence of DOX, TAC surgery caused substantial chamber dilation with a gradual decrease in contractility by 16 weeks. Cardiomyocytes showed a decline in contractility with abnormal Ca2+ handling during excitation-contraction (E-C) coupling. Reduced NCX1 activity was observed 8 weeks after TAC and was still apparent at 17 weeks. Induced NCX1 overexpression by DOX treatment starting 8 weeks after TAC returned NCX1 activity to pre-TAC levels and prevented chamber dilation with cardiac dysfunction. DOX treatment not only upregulated NCX1 expression in TAC-operated hearts but also returned L-type Ca2+ channel and sarcoplasmic reticulum (SR) Ca2+ ATPase expression levels to those in sham-operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca2+ release from the SR, and Ca2+ handling during E-C coupling was preserved 16 weeks after TAC surgery. In addition, DOX treatment attenuated the down-regulation of survival signalling and up-regulation of apoptosis signalling 16 weeks after TAC surgery. Conclusion 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.

Original languageEnglish
Pages (from-to)348-361
Number of pages14
JournalCardiovascular Research
Volume111
Issue number4
DOIs
Publication statusPublished - Sep 1 2016

Fingerprint

Constriction
Doxycycline
Pressure
Excitation Contraction Coupling
Heart Failure
Sarcoplasmic Reticulum
Dilatation
Calcium-Transporting ATPases
Cardiac Myocytes
Muscle Cells
Transgenic Mice
Up-Regulation
Down-Regulation
Apoptosis

Keywords

  • Cardiac pathological remodeling
  • Heart failure
  • Pressure overload
  • Sodium/calcium exchanger

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling. / Ujihara, Yoshihiro; Iwasaki, Keiichiro; Takatsu, Satomi; Hashimoto, Ken; Naruse, Keiji; Mohri, Satoshi; Katanosaka, Yuki.

In: Cardiovascular Research, Vol. 111, No. 4, 01.09.2016, p. 348-361.

Research output: Contribution to journalArticle

Ujihara, Yoshihiro ; Iwasaki, Keiichiro ; Takatsu, Satomi ; Hashimoto, Ken ; Naruse, Keiji ; Mohri, Satoshi ; Katanosaka, Yuki. / Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling. In: Cardiovascular Research. 2016 ; Vol. 111, No. 4. pp. 348-361.
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AU - Ujihara, Yoshihiro

AU - Iwasaki, Keiichiro

AU - Takatsu, Satomi

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AU - Naruse, Keiji

AU - Mohri, Satoshi

AU - Katanosaka, Yuki

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N2 - Aims Although increased Na+/Ca2+ exchanger 1 (NCX1) expression is observed during heart failure (HF), the pathological role of NCX1 during the progression of HF remains unclear. We examined alterations of NCX1 expression and activity in hearts after transverse aortic constriction (TAC) surgery and explored whether NCX1 influences pressure overload-induced pathological cardiac remodelling. Methods and results We generated novel transgenic mice in which NCX1 expression is controlled by a cardiac-specific, doxycycline (DOX)-dependent promoter. In the absence of DOX, TAC surgery caused substantial chamber dilation with a gradual decrease in contractility by 16 weeks. Cardiomyocytes showed a decline in contractility with abnormal Ca2+ handling during excitation-contraction (E-C) coupling. Reduced NCX1 activity was observed 8 weeks after TAC and was still apparent at 17 weeks. Induced NCX1 overexpression by DOX treatment starting 8 weeks after TAC returned NCX1 activity to pre-TAC levels and prevented chamber dilation with cardiac dysfunction. DOX treatment not only upregulated NCX1 expression in TAC-operated hearts but also returned L-type Ca2+ channel and sarcoplasmic reticulum (SR) Ca2+ ATPase expression levels to those in sham-operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca2+ release from the SR, and Ca2+ handling during E-C coupling was preserved 16 weeks after TAC surgery. In addition, DOX treatment attenuated the down-regulation of survival signalling and up-regulation of apoptosis signalling 16 weeks after TAC surgery. Conclusion 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.

AB - Aims Although increased Na+/Ca2+ exchanger 1 (NCX1) expression is observed during heart failure (HF), the pathological role of NCX1 during the progression of HF remains unclear. We examined alterations of NCX1 expression and activity in hearts after transverse aortic constriction (TAC) surgery and explored whether NCX1 influences pressure overload-induced pathological cardiac remodelling. Methods and results We generated novel transgenic mice in which NCX1 expression is controlled by a cardiac-specific, doxycycline (DOX)-dependent promoter. In the absence of DOX, TAC surgery caused substantial chamber dilation with a gradual decrease in contractility by 16 weeks. Cardiomyocytes showed a decline in contractility with abnormal Ca2+ handling during excitation-contraction (E-C) coupling. Reduced NCX1 activity was observed 8 weeks after TAC and was still apparent at 17 weeks. Induced NCX1 overexpression by DOX treatment starting 8 weeks after TAC returned NCX1 activity to pre-TAC levels and prevented chamber dilation with cardiac dysfunction. DOX treatment not only upregulated NCX1 expression in TAC-operated hearts but also returned L-type Ca2+ channel and sarcoplasmic reticulum (SR) Ca2+ ATPase expression levels to those in sham-operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca2+ release from the SR, and Ca2+ handling during E-C coupling was preserved 16 weeks after TAC surgery. In addition, DOX treatment attenuated the down-regulation of survival signalling and up-regulation of apoptosis signalling 16 weeks after TAC surgery. Conclusion 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.

KW - Cardiac pathological remodeling

KW - Heart failure

KW - Pressure overload

KW - Sodium/calcium exchanger

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