Altered Ca²⁺ handling by ryanodine receptor and Na⁺-Ca²⁺ exchange in the heart from ovariectomized rats: role of protein kinase A

Abstract

Kravtsov GM, Kam KW, Liu J, Wu S, Wong TM. Altered Ca 2ϩ handling by ryanodine receptor and Na ϩ -Ca 2ϩ exchange in the heart from ovariectomized rats: role of protein kinase A. Am J Physiol Cell Physiol 292: C1625-C1635, 2007. First published December 13, 2006; doi:10.1152/ajpcell.00368.2006.-Our previous study has demonstrated that ovariectomy (Ovx) significantly increased the left ventricular developed pressure (LVDP) and the maximal rate of developed pressure over time (ϮdP/dt max) in the isolated perfused rat heart and the effects were reversed by female sex hormone replacement. In the present investigation, we studied the effects of Ovx for 6 wk on Ca 2ϩ homeostasis that determines the contractile function. Particular emphasis was given to Ca 2ϩ handling by ryanodine receptor (RyR) and Na ϩ -Ca 2ϩ exchange (NCX ]i) in the heart. In addition, we determined the expression and contribution of protein kinase A (PKA) to the regulation of the aforementioned Ca 2ϩ handling proteins in Ovx rats. It was found that after Ovx there were 1) increased Ca 2ϩ fluxes via RyR and NCX, which were reversed not only by estrogen replacement, but more importantly by blockade of PKA; 2) an increased expression of PKA; and 3) no increase in expression of NCX and SERCA. We suggest that hyperactivities of RyR and NCX are a result of upregulation of PKA. The increased release of Ca 2ϩ through RyR and removal of Ca 2ϩ by NCX are believed to be responsible for the greater contractility and faster relaxation after Ovx. ovariectomy THERE IS INCREASING EVIDENCE that estrogen regulates the cardiac function by direct action on the myocardium. Ovariectomy (Ovx) has been shown to affect the cardiac contractility (5,22,27,28,37). A recent study from our laboratory (15) has also shown that Ovx for 6 wk significantly increased the left ventricular developed pressure (LVDP) and maximal rate of developed pressure over time (ϮdP/dt max ) in the isolated perfused rat heart and the effects were reversed by female sex hormone replacement. Moreover, the amplitude of the electrically induced intracellular Ca 2ϩ transient (E[Ca 2ϩ

Increased myocardial stiffness with maintenance of length-dependent calcium activation by female sex hormones in diabetic rats

“…Phosphorylation of titin has been hypothesized to alter myofilament stiffness, resulting in changes in lattice spacing and leading to changes in myofilament Ca 2ϩ sensitivity (14). Based on the previous reports from both our and another groups demonstrating an increase in ␤-adrenoceptor density and PKA expression in cardiac myocytes of OVX rats (22,38), female sex hormones may be able to regulate myofilament Ca 2ϩ activation through titin phosphorylation as well.…”

Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice

“…Review of the literature provides a basis for inferring that omega-3 may act at similar cellular targets to estrogen (7,18,27,33,47). Dietary omega-3 PUFA and estrogen have been both observed to modulate cardiomyocyte ion homeostasis, particularly the ionic fluxes involved in excitation-contraction coupling, and have been linked with intracellular Ca 2ϩ -dependent downstream signaling.…”

“…Systemic estrogen has also been shown to afford protection against arrhythmogenesis, ischemia-reperfusion injury, and myocardial hypertrophy (22,35,43). Various in vitro studies suggest that the biological actions and cellular targets of omega-3 PUFA and estrogen may be similar, suggesting that omega-3 PUFA may exert a greater effect in females after a period of estrogen withdrawal; albeit a possible convergence of action has not been directly investigated experimentally (7,18,27,33,47).…”

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…98 Similarly, the increase in Ca 2ϩ fluxes across the ryandine receptor and Na ϩ -Ca 2ϩ exchange in ovariectomized rats is reversed by estrogen treatment. 99 This latter effect of estrogen on Ca 2ϩ flux may be the result of the impact of estrogen on protein kinase A activity. 99 In highly aerobic tissues with high fatty acid flux like the heart, cellular lipid balance is critical to normal function.…”

“…99 This latter effect of estrogen on Ca 2ϩ flux may be the result of the impact of estrogen on protein kinase A activity. 99 In highly aerobic tissues with high fatty acid flux like the heart, cellular lipid balance is critical to normal function. Studies in mice that lack peroxisome proliferator-activator Figure 2.…”