Oestrogen confers cardioprotection by suppressing Ca2+/calmodulin-dependent protein kinase II.
OBJECTIVE
Oestrogen confers cardioprotection by down-regulating the beta(1)-adrenoceptor and suppressing the expression and activity of protein kinase A. We hypothesized that oestrogen may also protect the heart by suppressing Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), another signalling messenger activated by the beta(1)-adrenoceptor, that enhances apoptosis.


METHODS
We first determined the expression of CaMKII in the heart from sham and ovariectomized rats with and without oestrogen replacement. We then determined the effects of CaMKII inhibition (KN93, 2.5 micromolxL(-1)) in the presence or absence of 10(-7) molxL(-1) isoprenaline, a non-selective beta-adrenoceptor agonist. We also determined the percentage apoptosis in myocytes from rats in each group with or without beta-adrenoceptor stimulation.


RESULTS
Both CaMKIIdelta and phosphorylated CaMKII were up-regulated in the hearts from ovariectomized rats, and they were restored to normal by oestrogen replacement. The infarct size and lactate dehydrogenase release were significantly greater after ovariectomy. Similarly, cardiac contractility, the amplitude of the electrically induced intracellular Ca(2+) transient and the number of apoptotic cells were also greater in ovariectomized rats upon ischaemia/reperfusion in the presence or absence of isoprenaline. Most importantly, the responses to ischaemic insult in ovariectomized rats were reversed not only by oestrogen replacement, but by blockade of CaMKII with KN93.


CONCLUSIONS
Oestrogen confers cardioprotection at least partly by suppressing CaMKIIdelta. This effect of oestrogen on CaMKII is independent of the beta-adrenoceptor and occurs in addition to down-regulation of the receptor.
Department of Physiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Y
Y
Ma
W T
WT
Cheng
S
S
Wu
T M
TM
Wong
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001596:Benzylamines / Q000494:pharmacology; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D004343:Drug Implants; D004967:Estrogens / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010052:Ovariectomy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D020127:Recovery of Function; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000318:Adrenergic beta-Agonists; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004343:Drug Implants; D004967:Estrogens; D007545:Isoproterenol; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C517677:Camk2d protein, rat