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Women with functional ovaries have a lower cardiovascular risk than men and postmenopausal women. However, estrogen replacement therapy remains controversial. This study examined the effect of ovarian hormone deficiency and estrogen replacement on ventricular myocyte contractile function and PKB/Akt activation. Nulliparous female rats were subjected to bilateral ovariectomy (Ovx) or sham operation (sham). A subgroup of Ovx rats received estrogen ([E.sub.2]) replacement (40 [micro]g*[kg.sup.-1]* [day.sup.-1]) for 8 weeks. Mechanical and intracellular [Ca.sup.2+] properties were evaluated including peak shortening (PS), time to PS (TPS), time to 90% relengthening (T[R.sub.90]), maximal velocity of shortening/relengthening ([+ or -]dL/dt), fura 2 fluorescence intensity (FFI), and decay rate. Levels of sarco(endo)plasmic reticulum [Ca.sup.2+]-ATPase (SERCA2a), phospholamban (PLB), and Akt were assessed by Western blot. Ovx promoted body weight gain associated with reduced serum [E.sub.2] and uterine weight, all of which were abolished by [E.sub.2]. Ovx depressed PS and [+ or -] dL/dt, prolonged TPS, T[R.sub.90], and decay rate, and enhanced resting FFI, all of which, with the exception of TPS, were restored by [E.sub.2]. Ovx did not alter the levels of SERCA2a, PLB, and total Akt, but significantly reduced Akt activation [phosphorylated Akt (pAkt)], pAkt/Akt, and the SERCA2a-to-PLB ratio. These alterations in protein expression were restored by [E.sub.2]. [E.sub.2] enhanced PS and +dL/dt in vitro, which was abolished by the [E.sub.2] receptor antagonist ICI-182780. Ovx reduced myocyte [Ca.sup.2+] responsiveness and lessened stimulating frequency-induced decline in PS, both ablated by [E.sub.2]. These data suggest that mechanical and protein functions of ventricular myocytes are directly regulated by [E.sub.2]. ovariectomy; cardiac myocyte; contraction, intracellular [Ca.sup.2+]

Although senile plaques represent a defining hallmark of Alzheimer's disease (AD) brains their role in disease pathophysiology remains unclear. Plaque core constituents are proteolytically derived fibrillar aggregates of β-amyloid peptides [...]

Obesity is associated with an increased incidence of cardiovascular diseases such as hypertension, stroke, and congestive heart failure (1). Although it appears that cardiac function may be normal or enhanced [...]

Women with functional ovaries have a lower cardiovascular risk than men and postmenopausal women. However, estrogen replacement therapy remains controversial. This study examined the effect of ovarian hormone deficiency and estrogen replacement on ventricular myocyte contractile function and PKB/Akt activation. Nulliparous female rats were subjected to bilateral ovariectomy (Ovx) or sham operation (sham). A subgroup of Ovx rats received estrogen (E[sub 2]) replacement (40 μg·kgsup -1]. day[sup -1]) for 8 weeks. Mechanical and intracellular Ca[sup 2+] properties were evaluated including peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR[sub 90]), maximal velocity of shortening/relengthening (±dL/dt), fura 2 fluorescence intensity (FFI), and decay rate. Levels of sarco(endo)plasmic reticulum Ca[sup 2+]-ATPase (SERCA2a), phospholamban (PLB), and Akt were assessed by Western blot. Ovx promoted body weight gain associated with reduced serum E[sub 2] and uterine weight, all of which were abolished by E[sub 2]. Ovx depressed PS and ±dL/dt, prolonged TPS, TR[sub 90], and decay rate, and enhanced resting FFI, all of which, with the exception of TPS, were restored by E[sub 2]. Ovx did not alter the levels of SERCA2a, PLB, and total Akt, but significantly reduced Akt activation [phosphorylated Akt (pAkt)], pAkt/Akt, and the SERCA2ato-PLB ratio. These alteration in proton expression were restored by E[sub 2]. E[sub 2] enhanced PS and +dL/dt in vitro, which was abolished by the E[sub 2] receptor antagonist ICI-182780. Ovx reduced myocyte Ca[sup 2+] responsiveness and lessened stimulating frequency-induced decline in PS, both ablated by E[sub 2]. These data suggest that mechanical and proton functions of ventricular myocytes are directly regulated by E[sub 2]. [ABSTRACT FROM AUTHOR]

Ceramide, the metabolic product of signaling molecule sphingomyelin, has been implicated in cardiac Ca2+ regulation. To study the possible role of ceramide in the pathogenesis of diabetic cardiomyopathy, we examined the effects of ceramide on the cardiac contractility of cultured ventricular myocytes under control and simulated diabetic environments. Adult rat ventricular myocytes were maintained in normal (NG, 5.5 mM) or high glucose (HG, 25.5 mM) medium for 24 hr in the absence or presence of the membrane-permeant ceramide analog C2-ceramide, ceramide glucosyltransferase inhibitor D,L-threo-1-pheny-2-decanoylamino-3-morpholino-1-propanol (PDMP), or the inactive ceramide analog C2-dihydroceramide. Contractile indices analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (+/- dL/dt), and intracellular Ca2+ fura-2 fluorescence intensity (FFI). Myocytes maintained in HG medium displayed reduced PS and +/- dL/dt associated with prolonged TR90 and normal TPS compared to NG myocytes. Interestingly, the HG-induced mechanical dysfunctions were significantly attenuated by C2-ceramide or PDMP. C2-ceramide did not affect the myocyte mechanics in NG myocytes although PDMP shortened TPS without affecting any other indices. The HG-induced contractile abnormalities were not altered by inactive ceramide analog C2-dihydroceramide (except +/- dL/dt). Fura-2 fluorescence recording revealed that HG reduced baseline as well as stimulated intracellular Ca2+ levels, which may be abolished by both C2-ceramide and PDMP. These data suggest that alteration of ceramide signaling may play a role in the pathogenesis of diabetic cardiomyopathy.