Ca 2+ entry mode of Na +/Ca 2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction

Daisuke Kamimura, Tomohito Ohtani, Yasushi Sakata, Toshiaki Mano, Yasuharu Takeda, Shunsuke Tamaki, Yosuke Omori, Yasumasa Tsukamoto, Kazuharu Furutani, Yutaka Komiyama, Masamichi Yoshika, Hakuo Takahashi, Toshio Matsuda, Akemichi Baba, Satoshi Umemura, Takeshi Miwa, Issei Komuro, Kazuhiro Yamamoto

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

AimsLeft ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na +/K-ATPase and activate the Ca 2 entry mode of Na +/Ca 2 exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. Methods and results(i) Dahl salt-sensitive rats fed 8 NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in SpragueDawley rats. (iii) Ouabain elevated intracellular Ca 2 concentration through the entry of extracellular Ca 2, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced 3H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening.ConclusionDigitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

Original languageEnglish (US)
Pages (from-to)1408-1416
Number of pages9
JournalEuropean Heart Journal
Volume33
Issue number11
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

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Sodium-Calcium Exchanger
Heart Failure
Fibrosis
Ouabain
Therapeutics
Fibroblasts
Inbred Dahl Rats
Mitogen-Activated Protein Kinase 1
Proline
Cardiovascular Diseases
Collagen
Survival Rate
Phosphorylation
Urine
Pharmacology
Ions
Diet
Blood Pressure
Hypertension
Phenotype

Keywords

  • Diastole
  • Digitalis-like factors
  • Fibrosis
  • Heart failure
  • Na /Ca exchanger

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ca 2+ entry mode of Na +/Ca 2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction. / Kamimura, Daisuke; Ohtani, Tomohito; Sakata, Yasushi; Mano, Toshiaki; Takeda, Yasuharu; Tamaki, Shunsuke; Omori, Yosuke; Tsukamoto, Yasumasa; Furutani, Kazuharu; Komiyama, Yutaka; Yoshika, Masamichi; Takahashi, Hakuo; Matsuda, Toshio; Baba, Akemichi; Umemura, Satoshi; Miwa, Takeshi; Komuro, Issei; Yamamoto, Kazuhiro.

In: European Heart Journal, Vol. 33, No. 11, 01.06.2012, p. 1408-1416.

Research output: Contribution to journalArticle

Kamimura, D, Ohtani, T, Sakata, Y, Mano, T, Takeda, Y, Tamaki, S, Omori, Y, Tsukamoto, Y, Furutani, K, Komiyama, Y, Yoshika, M, Takahashi, H, Matsuda, T, Baba, A, Umemura, S, Miwa, T, Komuro, I & Yamamoto, K 2012, 'Ca 2+ entry mode of Na +/Ca 2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction', European Heart Journal, vol. 33, no. 11, pp. 1408-1416. https://doi.org/10.1093/eurheartj/ehr106
Kamimura, Daisuke ; Ohtani, Tomohito ; Sakata, Yasushi ; Mano, Toshiaki ; Takeda, Yasuharu ; Tamaki, Shunsuke ; Omori, Yosuke ; Tsukamoto, Yasumasa ; Furutani, Kazuharu ; Komiyama, Yutaka ; Yoshika, Masamichi ; Takahashi, Hakuo ; Matsuda, Toshio ; Baba, Akemichi ; Umemura, Satoshi ; Miwa, Takeshi ; Komuro, Issei ; Yamamoto, Kazuhiro. / Ca 2+ entry mode of Na +/Ca 2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction. In: European Heart Journal. 2012 ; Vol. 33, No. 11. pp. 1408-1416.
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T1 - Ca 2+ entry mode of Na +/Ca 2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction

AU - Kamimura, Daisuke

AU - Ohtani, Tomohito

AU - Sakata, Yasushi

AU - Mano, Toshiaki

AU - Takeda, Yasuharu

AU - Tamaki, Shunsuke

AU - Omori, Yosuke

AU - Tsukamoto, Yasumasa

AU - Furutani, Kazuharu

AU - Komiyama, Yutaka

AU - Yoshika, Masamichi

AU - Takahashi, Hakuo

AU - Matsuda, Toshio

AU - Baba, Akemichi

AU - Umemura, Satoshi

AU - Miwa, Takeshi

AU - Komuro, Issei

AU - Yamamoto, Kazuhiro

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N2 - AimsLeft ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na +/K-ATPase and activate the Ca 2 entry mode of Na +/Ca 2 exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. Methods and results(i) Dahl salt-sensitive rats fed 8 NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in SpragueDawley rats. (iii) Ouabain elevated intracellular Ca 2 concentration through the entry of extracellular Ca 2, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced 3H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening.ConclusionDigitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

AB - AimsLeft ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na +/K-ATPase and activate the Ca 2 entry mode of Na +/Ca 2 exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. Methods and results(i) Dahl salt-sensitive rats fed 8 NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in SpragueDawley rats. (iii) Ouabain elevated intracellular Ca 2 concentration through the entry of extracellular Ca 2, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced 3H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening.ConclusionDigitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

KW - Diastole

KW - Digitalis-like factors

KW - Fibrosis

KW - Heart failure

KW - Na /Ca exchanger

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