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NHE-1 participates in isoproterenol-induced downregulation of SERCA2a and development of cardiac remodeling in rat hearts.

Abstract
Impaired Ca(2+) handling is one of the main characteristics in heart failure patients. Recently, we reported abnormal expressions of Ca(2+)-handling proteins in isoproterenol (ISO)-induced hypertrophied rat hearts. On the other hand, Na(+)/H(+) exchanger (NHE)-1 inhibitor has been demonstrated to exert beneficial effects in ischemic-reperfusion injury and in the development of cardiac remodeling. The aims of the present study are to investigate the role of NHE-1 on Ca(2+) handling and development of cardiac hypertrophy in ISO-infused rats. Male Wistar rats were randomly divided into vehicle [control (CTL)] and ISO groups without or with pretreatment with a selective NHE-1 inhibitor, BIIB-723. ISO infusion for 1 wk significantly increased the ratios of heart to body weight and left ventricle (LV) to body weight and collagen accumulation. All of these increases were antagonized by coadministration with BIIB-723. The ISO-induced significant increase in LV wall thickness was suppressed significantly (P < 0.05) by BIIB-723. ISO-induced decreases in cardiac stroke volume and a total mechanical energy per beat index, systolic pressure-volume area at midrange LV volume, were normalized by BIIB-723. The markedly higher expression of NHE-1 protein in the ISO group than that in CTL group was suppressed (P < 0.05) by BIIB-723. Surprisingly, ISO induced downregulation of the important Ca(2+)-handling protein sarcoplasmic reticulum Ca(2+)-ATPase 2a, the expression of which was also normalized by BIIB-723 without changes in phosphorylated phospholamban (PLB)/PLB expression. We conclude that NHE-1 contributes to ISO-induced abnormal Ca(2+) handling associated with cardiac hypertrophy. Inhibition of NHE-1 ameliorates cardiac Ca(2+)-handling impairment and prevents the development of cardiac dysfunction in ISO-infused rats.
AuthorsMunetaka Shibata, Daisuke Takeshita, Koji Obata, Shinichi Mitsuyama, Haruo Ito, Guo-Xing Zhang, Miyako Takaki
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 301 Issue 5 Pg. H2154-60 (Nov 2011) ISSN: 1522-1539 [Electronic] United States
PMID21856903 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Atp2a2 protein, rat
  • BIIB 723
  • Calcium-Binding Proteins
  • Guanidines
  • Slc9a1 protein, rat
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • phospholamban
  • Collagen
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Isoproterenol
Topics
  • Animals
  • Calcium Signaling (drug effects)
  • Calcium-Binding Proteins (metabolism)
  • Cardiomegaly (chemically induced, enzymology, pathology, physiopathology, prevention & control)
  • Collagen (metabolism)
  • Disease Models, Animal
  • Down-Regulation
  • Guanidines (pharmacology)
  • Heart Rate
  • Isoproterenol
  • Male
  • Myocardium (enzymology, pathology)
  • Phosphorylation
  • Rats
  • Rats, Wistar
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)
  • Stroke Volume
  • Time Factors
  • Ventricular Function, Left
  • Ventricular Remodeling (drug effects)

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