title: 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.
authors.affiliation: Department of Physiology II, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Munetaka
authors.initials: M
authors.lastname: Shibata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takeshita
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mitsuyama
authors.forename: Haruo
authors.initials: H
authors.lastname: Ito
authors.forename: Guo-Xing
authors.initials: GX
authors.lastname: Zhang
authors.forename: Miyako
authors.initials: M
authors.lastname: Takaki
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate; D007545:Isoproterenol; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D003094:Collagen; D006146:Guanidines; D007545:Isoproterenol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D000099211:Phospholamban; C506948:Atp2a2 protein, rat; C522118:BIIB 723; C452850:Slc9a1 protein, rat