title: Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling.
abstract: Although increased Na(+)/Ca(2+) 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.
  
  
  
  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 Ca(2+) 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 Ca(2+) channel and sarcoplasmic reticulum (SR) Ca(2+) ATPase expression levels to those in sham-operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca(2+) release from the SR, and Ca(2+) 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.
  
  
  
  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.
authors.affiliation: Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan Department of Physiology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ujihara
authors.affiliation: Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Takatsu
authors.affiliation: Department of Physiology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Naruse
authors.affiliation: Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan Department of Physiology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mohri
authors.affiliation: Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan ytanigu@md.okayama-u.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katanosaka
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Cardiac pathological remodeling; Heart failure; Pressure overload; Sodium/calcium exchanger