Ovariectomy enhances SR Ca2+ release and increases Ca2+ spark amplitudes in isolated ventricular myocytes

Fares, Elias; Parks, Randi J.; MacDonald, Jennifer; Egar, Jeanne; Howlett, Susan E.

doi:10.1016/j.yjmcc.2011.09.002

Cited by 35 publications

(36 citation statements)

References 55 publications

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“…Figure 8A shows representative caffeine-induced Ca 2+ transients recorded from sham and OVX myocytes. The profile of these responses is comparable to caffeine-induced transients recorded under similar conditions in our previous studies [10,11,14,15]. Mean data showed that caffeine-induced Ca 2+ transients were 90% larger in OVX myocytes compared to sham controls (Figure 8B).…”

Section: Resultssupporting

confidence: 85%

“…[20,21]. We have shown that this is not due to an increase in Ca 2+ current, but arises from increased sarcoplasmic reticulum (SR) Ca 2+ release as a consequence of increased SR stores and larger Ca 2+ sparks [15]. These findings suggest that removal of ovarian estrogen in young adult females enhances SR Ca 2+ release and leads to Ca 2+ transients and contractions that are similar to those seen in myocytes from young adult males.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that Ca 2+ transients and contractions are smaller and slower in ventricular myocytes from young adult female rats when compared to age-matched males [9,13,14]. However, bilateral ovariectomy (OVX) of young adult females increases the speed and magnitude of Ca 2+ transients and contractions compared to sham-operated controls [15-19] but cf. [20,21].…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Ovariectomy on Calcium Homeostasis and Myofilament Calcium Sensitivity in the Aging Mouse Heart

et al. 2013

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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.

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Section: Resultssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Impact of Ovariectomy on Calcium Homeostasis and Myofilament Calcium Sensitivity in the Aging Mouse Heart

et al. 2013

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“…It has been suggested that female cardiomyocytes operate at lower levels of intracellular Ca 2+ than those of males, particularly under inotropic conditions (31). This difference in Ca 2+ homeostasis may be related to the fact that estrogen suppresses the L-type Ca 2+ current (32,33) and may reduce the amount of Ca 2+ released from the sarcoplasmic reticulum (SR) (34), which was shown to be larger in myocytes from OVX rats (35). Not only cardiomyocyte contraction, but relaxation may also be affected by estrogen via altered Ca 2+ re-uptake into the SR and modified Ca 2+ efflux via increased sarcolemmal Na + /Ca 2+ exchange (36).…”

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confidence: 99%

Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats

et al. 2014

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AimTo assess how ovarian-derived sex hormones (in particular progesterone) modify the effects of single acute stress on the mechanical and biochemical properties of left ventricular cardiomyocytes in the rat.MethodsNon-ovariectomized (control, n = 8) and ovariectomized (OVX, n = 8) female rats were kept under normal conditions or were exposed to stress (control-S, n = 8 and OVX-S, n = 8). Serum progesterone levels were measured using a chemiluminescent immunoassay. Left ventricular myocardial samples were used for isometric force measurements and protein analysis. Ca2+-dependent active force (Factive), Ca2+-independent passive force (Fpassive), and Ca2+-sensitivity of force production were determined in single, mechanically isolated, permeabilized cardiomyocytes. Stress- and ovariectomy-induced alterations in myofilament proteins (myosin-binding protein C [MyBP-C], troponin I [TnI], and titin) were analyzed by sodium dodecyl sulfate gel electrophoresis using protein and phosphoprotein stainings.ResultsSerum progesterone levels were significantly increased in stressed rats (control-S, 35.6 ± 4.8 ng/mL and OVX-S, 21.9 ± 4.0 ng/mL) compared to control (10 ± 2.9 ng/mL) and OVX (2.8 ± 0.5 ng/mL) groups. Factive was higher in the OVX groups (OVX, 25.9 ± 3.4 kN/m2 and OVX-S, 26.3 ± 3.0 kN/m2) than in control groups (control, 16.4 ± 1.2 kN/m2 and control-S, 14.4 ± 0.9 kN/m2). Regarding the potential molecular mechanisms, Factive correlated with MyBP-C phosphorylation, while myofilament Ca2+-sensitivity inversely correlated with serum progesterone levels when the mean values were plotted for all animal groups. Fpassive was unaffected by any treatment.Conclusion Stress increases ovary-independent synthesis and release of progesterone, which may regulate Ca2+-sensitivity of force production in left ventricular cardiomyocytes. Stress and female hormones differently alter Ca2+-dependent cardiomyocyte contractile force production, which may have pathophysiological importance during stress conditions affecting postmenopausal women.

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“…Female cardiomyocytes function at a lower operational Ca 2ϩ level compared with male cardiomyocytes (27). Most evidence indicates that sex steroids have reciprocal actions on myocyte Ca 2ϩ and contraction, with estrogen suppressing and testosterone stimulating Ca 2ϩ cycling and contractile function (26,28,29). A role for endogenous aromatase influence on cardiomyocyte function and Ca 2ϩ handling has not been previously identified.…”

Section: Ablating Aromatase Activity Up-regulates Basal Cardiomyocytementioning

confidence: 99%

Myocardial and Cardiomyocyte Stress Resilience Is Enhanced in Aromatase-Deficient Female Mouse Hearts Through CaMKIIδ Activation

et al. 2015

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The role of sex steroids in cardioprotection is contentious, with large clinical trials investigating hormone supplementation failing to deliver outcomes expected from observational studies. Mechanistic understanding of androgen/estrogen myocardial actions is lacking. Using a genetic model of aromatase tissue deficiency (ArKO) in female mice, the goal of this investigation was to evaluate the capacity of a shift in cardiac endogenous steroid conversion to influence ischemia-reperfusion resilience by optimizing cardiomyocyte Ca2+ handling responses. In isolated normoxic cardiomyocytes, basal Ca2+ transient amplitude and extent of shortening were greater in ArKO myocytes, with preservation of diastolic Ca2+ levels. Isolated ArKO cardiomyocytes exposed to a high Ca2+ load exhibited greater Ca2+ transient and contractile amplitudes, associated with a greater postrest spontaneous sarcoplasmic reticulum Ca2+ load-release. Microarray differential gene expression analysis of normoxic ventricular tissues from ArKO vs wild-type identified a significant influence of aromatase on genes involved in cardiac Ca2+ handling and signaling [including calmodulin dependent kinase II (CaMKII)-δ], myofilament structure and function, glucose uptake and signaling, and enzymes controlling phosphorylation-specific posttranslational modification status. CaMKII expression was not changed in ventricular tissues, although CaMKIIδ activation and phosphorylation of downstream targets was enhanced in ArKO hearts subjected to ischemia-reperfusion. Overall, this investigation shows that relative withdrawal of estrogen in favor of testosterone through genetically induced tissue aromatase deficiency in females modifies the gene expression profile to effect inotropic support via optimized Ca2+ handling in response to stress, with a modest impact on basal function. Consideration of aromatase inhibition, acutely or chronically, may have a role in cardioprotection, of particular relevance to women.

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Ovariectomy enhances SR Ca2+ release and increases Ca2+ spark amplitudes in isolated ventricular myocytes

Cited by 35 publications

References 55 publications

The Impact of Ovariectomy on Calcium Homeostasis and Myofilament Calcium Sensitivity in the Aging Mouse Heart

The Impact of Ovariectomy on Calcium Homeostasis and Myofilament Calcium Sensitivity in the Aging Mouse Heart

Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats

Myocardial and Cardiomyocyte Stress Resilience Is Enhanced in Aromatase-Deficient Female Mouse Hearts Through CaMKIIδ Activation

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