title: Ca2+ entry mode of Na+/Ca2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction.
abstract: OBJECTIVE
  Left 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.
  
  
  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 Sprague-Dawley 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 (3)H-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.
  
  
  CONCLUSIONS
  Digitalis-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.
authors.affiliation: Department of Cardiovascular Medicine,  Osaka University Graduate School of Medicine, Suita,  Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.forename: Tomohito
authors.initials: T
authors.lastname: Ohtani
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Takeda
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tamaki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Omori
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Furutani
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Komiyama
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yoshika
authors.forename: Hakuo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002298:Cardenolides / Q000378:metabolism* / Q000652:urine; D005355:Fibrosis / Q000503:physiopathology / Q000628:therapy; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000473:pathology*; D058628:Myofibroblasts / Q000378:metabolism; D010042:Ouabain / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000378:metabolism* / Q000652:urine; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013318:Stroke Volume / Q000502:physiology; D013977:Tibia / Q000033:anatomy & histology
chemical_list: D002298:Cardenolides; D012503:Saponins; D019831:Sodium-Calcium Exchanger; C034504:digoxin-like factors; D010042:Ouabain; D002118:Calcium