title: Transgenic expression of sarcoplasmic reticulum Ca(2+) atpase modifies the transition from hypertrophy to early heart failure.
abstract: To examine the contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) to early heart failure, we subjected transgenic (TG) mice expressing SERCA2a gene and wild-type (WT) mice to aortic stenosis (AS) for 7 weeks. At an early stage of hypertrophy (4-week AS), in vivo hemodynamic and echocardiographic indices were similar in TG and WT mice. By 7 weeks of AS, which is the stage of early failure in this model, TG mice with AS had lower mortality than WT mice with AS (6.7% versus 29%). The magnitude of left ventricular (LV) hypertrophy was similar in WT and TG 7-week AS mice. In vivo LV systolic function was higher in TG than in WT 7-week AS mice. In LV myocytes loaded with fluo-3, fractional cell shortening and the amplitude of the [Ca(2+)](i) transients were higher in TG than in WT 7-week AS mice under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca(2+)](o), 25 degrees C). The rates of relengthening and decay in [Ca(2+)](i) were faster in TG than in WT 7-week AS myocytes. In myocytes from WT 7-week AS compared with sham-operated WT mice, contractile reserve in response to rapid pacing was depressed with impaired augmentation of both peak-systolic [Ca(2+)](i) and the SR Ca(2+) load. In contrast, contractile reserve and the capacity to augment SR Ca(2+) load were maintained in TG 7-week AS mice. SERCA2a protein levels were depressed in WT 7-week AS mice, but were preserved in TG 7-week AS mice. These data suggest that defective SR Ca(2+) loading contributes to the onset of contractile failure in animals with chronic pressure overload.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: X
authors.initials: X
authors.lastname: Yan
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.forename: W J
authors.initials: WJ
authors.lastname: Manning
authors.forename: W H
authors.initials: WH
authors.lastname: Dillmann
authors.forename: B H
authors.initials: BH
authors.lastname: Lorell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004452:Echocardiography; D005838:Genotype; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology*; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban