The impact of ovariectomy on calcium homeostasis and myofilament calcium sensitivity in the aging mouse heart.
This study determined whether deficiency of ovarian estrogen starting very early in life promoted age-associated Ca(2+) dysregulation and contractile dysfunction in isolated ventricular myocytes. Myocytes were isolated from anesthetized C57BL/6 female mice. Animals received an ovariectomy or sham-operation at one month and were aged to ~24 months. Excitation-contraction coupling parameters were compared in fura-2 loaded myocytes (37°C). While Ca(2+) transients were larger and faster in field-stimulated myocytes from ovariectomized mice, ovariectomy had no effect on peak fractional shortening. Similarly, ovariectomy had no effect on fractional shortening measured in vivo by echocardiography (values were 60.5 ± 2.9 vs. 60.3 ± 2.5% in sham and ovariectomized, respectively; n=5 mice/group). Ovariectomy did decrease myofilament Ca(2+) sensitivity, as evidenced by a 26% increase in the Ca(2+) required to activate actomyosin MgATPase in ovariectomized hearts. Larger Ca(2+) transients were attributable to a 48% increase in peak Ca(2+) current, along with an increase in the amplitude, width and frequency of Ca(2+) sparks measured in fluo-4 loaded myocytes. These changes in Ca(2+) handling were not due to increased expression of Ca(2+) channels (Cav1.2), sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) or Na(+)-Ca(2+) exchanger in ovariectomized hearts. However, ovariectomy increased sarcoplasmic reticulum Ca(2+) stores by ~90% and promoted spontaneous Ca(2+) release from the sarcoplasmic reticulum when compared to sham controls. These observations demonstrate that long-term ovariectomy promotes intracellular Ca(2+) dysregulation, reduces myofilament Ca(2+) sensitivity and increases spontaneous Ca(2+) release in the aging female heart.
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Elias
E
Fares
W Glen
WG
Pyle
Gibanananda
G
Ray
Robert A
RA
Rose
Eileen M
EM
Denovan-Wright
Robert P
RP
Chen
Susan E
SE
Howlett
D000200:Action Potentials; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D056966:Excitation Contraction Coupling; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism*; D010052:Ovariectomy; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D002118:Calcium