title: Cardiac-specific overexpression of a high Ca2+ affinity mutant of SERCA2a attenuates in vivo pressure overload cardiac hypertrophy.
abstract: In cardiomyocytes, calcium plays important roles as a signal in cardiac hypertrophy and contraction-relaxation cycling. Elevation of Ca2+ concentration in myoplasm is associated with the onset and progression of hypertrophy as well as the enhancement of contractility. The cardiac Ca2+ ATPase (SERCA2a) of the sarcoplasmic reticulum plays a dominant role in lowering cytoplasmic calcium levels during relaxation and is regulated by phospholamban (PLN). To examine whether the modulation of SERCA2a activity results in the attenuation of cardiac hypertrophy and enhancement of contractility, we generated transgenic mice (TG) overexpressing a high calcium affinity SERCA2a mutant (K397/400E), lacking a functional association with PLN. In the TG hearts, the apparent affinity of SERCA2a for Ca2+ significantly increased compared with their nontransgenic littermate controls. The TG showed increased contraction and relaxation, with increases in the amplitude of Ca2+ transient and rapid Ca2+ decay. Upon induction of pressure overload by transverse aortic constriction, the TG developed less cardiac hypertrophy than littermate controls did. The activation of Ca2+-sensitive protein kinase C by pressure overload was significantly attenuated in the TG hearts. Our findings indicate an association of SERCA2a activity with cardiac hypertrophy and thus a new therapeutic target for the prevention and treatment of cardiac hypertrophy.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Moto-o
authors.initials: MO
authors.lastname: Date
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hongo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusakari
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurihara
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Michihiko
authors.initials: M
authors.lastname: Tada
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D003250:Constriction; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000628:therapy*; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D011312:Pressure; D011493:Protein Kinase C / Q000032:analysis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D011493:Protein Kinase C; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium