Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice

Influx of Ca2+ into myocytes via Na+/Ca2+ exchange may be stimulated by the high levels of intracellular Na+ and the changes in membrane potential kno wn to occur during ischemia/reperfusion. This increased influx could, in tu rn, lead to Ca2+ overload and injury. Overexpression of the cardiac Na+/Ca2 + exchanger therefore may increase susceptibility to ischemia/reperfusion i njury. To test this hypothesis, the hearts of male and female transgenic mi ce, overexpressing the Na+/Ca2+ exchange protein, and hearts of their wild- type littermates, were perfused with Krebs-Henseleit buffer and subjected t o 20 minutes of ischemia and 40 minutes of reperfusion. Preischemic left ve ntricular developed pressures and +dP/dt(max), as well as -dP/dt(min), were higher in the male transgenic hearts compared with wild-type, implying a r ole for Na+/Ca2+ exchange in the contraction, as well as the relaxation, ph ases of the cardiac beat. Postischemic function was lower in male transgeni c than in male wild-type hearts (7+/-2% versus 32+/-6% of preischemic funct ion), but there was no difference between female transgenic and female wild -type hearts, both at approximate to 30% of preischemic function. To assess whether this male/female difference was due to female-specific hormones su ch as estrogen, the hearts of bilaterally ovariectomized and sham-operated transgenic females were subjected to the same protocol. The functional reco veries of ovariectomized female transgenic hearts were lower (17+/-3% of pr eischemic function) than those of wild-type and sham-operated transgenic fe males. The lower postischemic functional recovery in the male transgenic an d female ovariectomized transgenic hearts correlated with lower recoveries of the energy metabolites, ATP and phosphocreatine, as measured by P-31 nuc lear magnetic resonance spectroscopy. Alternans were observed during reperf usion in male transgenic and female ovariectomized transgenic hearts only, consistent with intracellular Ca2+ overload. Western analyses showed that a lterations in the expression of the Na+/Ca2+ exchange or L-type Ca2+ channe l proteins were not responsible for the protection observed in the female t ransgenic hearts. In conclusion, in males, overexpression of the Na+/Ca2+ e xchanger reduced postischemic recovery of both contractile function and ene rgy metabolites, indicating that the Na+/Ca2+ exchanger may play a role in ischemia/reperfusion injury. From the studies of females, however, it appea rs that this exacerbation of ischemia/reperfusion injury by overexpression of the Na+/Ca2+ exchanger can be overcome partially by female-specific horm ones such as estrogen.