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This dissertation, Effect of Ovariectomy and Estrogen Replacement on the {221}-Adrenergicreceptor Signaling Pathway and Intracellular Ca2 Homeostasis in Therat Heart by Wan-lung, Kenneth, Kam, 甘雲龍, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of the thesis entitled Effect of ovariectomy and estrogen replacement on the 2+ β-adrenergic receptor signaling pathway and intracellular Ca homeostasis in the rat heart submitted by Mr. Kam Wan Lung for the Degree of Doctor of Philosophy at the University of Hong Kong in January, 2005 Estrogen protects the heart against ischaemic insults and decreases the cardiac contractility. There is evidence that estrogen down-regulates β -adrenergic receptor (β -AR) and affects 1 1 2+ 2+ intracellular Ca ([Ca ]) homeostasis. It was hypothesized that estrogen might confer cardioprotection and decrease contractility by suppressing the expression of β -AR, altering its 2+ signaling mechanism, and affecting the [Ca ] homeostasis. Three series of experiments were conducted to address the chronic effects of estrogen on 1) the expression of β -AR, 2) the signaling 2+ intermediates mediating the action of β -AR activation and 3) [Ca ] homeostasis. These were 1 i correlated with the effects of estrogen on injury in response to ischaemic insult and/or contractile functions. In order to determine the action of estrogen on the myocardium, two in vitro preparations, the isolated perfused heart and isolated ventricular myocytes, were used. Ovariectomy (Ovx) was performed to remove the source of estrogen and the cardiac responses were compared with those from sham control and Ovx rats with estrogen replacement (Ovx+E ). The first important observation of the present study is that the cardioprotective effect of estrogen is due to its direct suppressive effect on the enhanced β -AR expression in the heart from Ovx rats, which in turn reduces the injury upon β-AR stimulation during ischaemia. This is based on two Iobservations. Myocardial infarct size was significantly greater in Ovx than in the sham and Ovx+E rats upon β-AR activation during ischaemia. There was a positive correlation between the infarct size and the expression level of β -AR. Furthermore, incubation of ventricular myocytes from Ovx rats with -9 10 M estrogen for 24 h, which significantly reduced the expression of β -AR, was accompanied by -9 cardioprotection. On the other hand, incubation of the myocytes with 10 M estrogen for 12h neither affected the β -AR expression nor reduced cardiac injury in response to ischaemic insults. The observation is evidence of a causal relationship between β -AR and cardiac injury. The second main finding is that both the basal and isoproterenol (Iso)-induced protein kinase A (PKA) activity were significantly higher in the heart from Ovx than those from the sham and Ovx+E rats. This was accompanied by a significantly higher basal and Iso-stimulated increase 2+ in L-type Ca channel (CaCh) activity. Blockade of PKA with a selective inhibitor, KT5720, at a concentration that reduced the effect of PKA on basal CaCh activity to that of the sham control, significantly inhibited the Iso-stimulated increase in CaCh activity in all three groups of rats and the inhibition was significantly greater in the Ovx rat than in the other two groups of rats, indicating a greater contribution of PKA on β-AR stimulated increase in CaCh activity in the heart from the Ovx rats. The result indicated that estrogen suppresses PKA a

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