Abstract
This study determined whether deficiency of ovarian estrogen starting very early in life promoted age-associated Ca2+ 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 Ca2+ 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 Ca2+ sensitivity, as evidenced by a 26% increase in the Ca2+ required to activate actomyosin MgATPase in ovariectomized hearts. Larger Ca2+ transients were attributable to a 48% increase in peak Ca2+ current, along with an increase in the amplitude, width and frequency of Ca2+ sparks measured in fluo-4 loaded myocytes. These changes in Ca2+ handling were not due to increased expression of Ca2+ channels (Cav1.2), sarcoplasmic reticulum Ca2+ ATPase (SERCA2) or Na+-Ca2+ exchanger in ovariectomized hearts. However, ovariectomy increased sarcoplasmic reticulum Ca2+ stores by ~90% and promoted spontaneous Ca2+ release from the sarcoplasmic reticulum when compared to sham controls. These observations demonstrate that long-term ovariectomy promotes intracellular Ca2+ dysregulation, reduces myofilament Ca2+ sensitivity and increases spontaneous Ca2+ release in the aging female heart.
Highlights
Studies in humans have shown that cardiac contractile function declines with age, even in the absence of overt cardiovascular disease [1,2]
Ventricle weight and ventricle-to-body weight ratios were similar in the two groups (Table 1), while uterine dry weights were significantly reduced in OVX mice (Table 1)
These findings show that while sham and OVX aged females were similar in weight and had similar heart sizes, OVX caused marked uterine atrophy
Summary
Studies in humans have shown that cardiac contractile function declines with age, even in the absence of overt cardiovascular disease [1,2]. Studies in intact hearts and cardiac tissues from aged rats show that the ability to augment force in response to positive inotropic stimuli is compromised in the aging heart [2] This age-related decrease in cardiac contractile function is due, at least in part, to a decrease in the ability of individual ventricular myocytes to contract [3,4,5,6]. Previous work from our laboratory and others has shown that the ability of individual ventricular myocytes to contract declines with age in male but not female rats and mice [9,10,11] This arises as a consequence of a reduction in the magnitude of the Ca2+ transient required to initiate contraction [9,10,11]. Little is known about the influence of sex steroid hormones such as estrogen on cardiac Ca2+ homeostasis in the setting of aging
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