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Oestrogen confers cardioprotection by suppressing Ca 2+ /calmodulin‐dependent protein kinase II
Author(s) -
Ma Y,
Cheng WT,
Wu S,
Wong TM
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00212.x
Subject(s) - cardioprotection , endocrinology , medicine , isoprenaline , ovariectomized rat , agonist , protein kinase a , contractility , chemistry , stimulation , kinase , calmodulin , phospholamban , staurosporine , receptor , biology , estrogen , calcium , ischemia , biochemistry
Background and purpose: Oestrogen confers cardioprotection by down‐regulating the β 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 β 1 ‐adrenoceptor, that enhances apoptosis. Experimental approach: 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 µmol·L −1 ) in the presence or absence of 10 −7 mol·L −1 isoprenaline, a non‐selective β‐adrenoceptor agonist. We also determined the percentage apoptosis in myocytes from rats in each group with or without β‐adrenoceptor stimulation. Key results: Both CaMKIIδ 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 and implications: Oestrogen confers cardioprotection at least partly by suppressing CaMKIIδ. This effect of oestrogen on CaMKII is independent of the β‐adrenoceptor and occurs in addition to down‐regulation of the receptor.