摘要
Background
Cardiovascular disease mortality increases rapidly after menopause by poorly defined mechanisms.Objective
<p>Because mitochondrial function and Cap>2+p> sensitivity are important regulators of cell death after myocardial ischemia, we sought to determine whether aging and/or estrogen deficiency (ovariectomy) increased mitochondrial Cap>2+p> sensitivity.Methods
<p>Mitochondrial respiration was measured in ventricular mitochondria isolated from adult (6 months; n = 26) and aged (24 months; n = 25), intact or ovariectomized female rats using the substrates 伪-ketoglutarate/malate (complex I); succinate/rotenone (complex II); ascorbate/N,N,N鈥?N鈥?tetramethyl-p-phenylenediamine/antimycin (complex IV). State 2 and 3 respiration was initiated by sequential addition of mitochondria and adenosine diphosphate. Cap>2+p> sensitivity was assessed by Cap>2+p>-induced swelling of de-energized mitochondria and reduction in state 3 respiration. Propylpyrazole triol (PPT) was administered intraperitoneally 45 minutes before euthanasia to assess mitochondrial protective effects through estrogen receptor (ER) 伪 activation.Results
<p>Aging decreased the respiratory control index (RCI; state 3/state 2) for complexes I and II by 12%and 8%, respectively, independent of ovary status (P < 0.05). Of interest, Cap>2+p> induced a greater decrease (18%-30%; P < 0.05) in complex I state 3 respiration in aged and ovariectomized animals, and mitochondrial swelling occurred twice as quickly in aged (vs adult) female rats (P < 0.05). Pretreatment with PPT increased RCI by 8%and 7%at complexes I and II, respectively (P < 0.05) but surprisingly increased Cap>2+p> sensitivity.Conclusions
<p>Age-dependent decreases in RCI and sensitization to Cap>2+p> may explain in part the age-associated reductions in female ischemic tolerance; however, protection afforded by ER agonism involves more complex mechanisms.
