© 1998 American Heart Association, Inc.
Original Contributions |
Overexpression of the Cardiac Na+/Ca2+ Exchanger Increases Susceptibility to Ischemia/Reperfusion Injury in Male, but Not Female, Transgenic Mice
From the National Institute of Environmental Health Sciences (H.R.C., E.M.), Research Triangle Park, NC; Cardiovascular Research Laboratories, UCLA School of Medicine, MacDonald Research Laboratories (L.L., K.D.P.), Los Angeles, Calif; and the Department of Pathology, Duke University (C.S.), Durham, NC.
Correspondence to Heather R. Cross, Mail Drop D2-03, NIEHS, Research Triangle Park, NC 27709. E-mail cross{at}niehs.nih.gov
Abstract—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 known to occur
during ischemia/reperfusion. This increased influx could, in
turn, lead to Ca2+ overload and injury. Overexpression of
the cardiac Na+/Ca2+ exchanger therefore may
increase susceptibility to ischemia/reperfusion injury. To test
this hypothesis, the hearts of male and female transgenic mice,
overexpressing the Na+/Ca2+ exchange protein,
and hearts of their wild-type littermates, were perfused with
Krebs-Henseleit buffer and subjected to 20 minutes of ischemia
and 40 minutes of reperfusion. Preischemic left
ventricular developed pressures and +dP/dtmax,
as well as -dP/dtmin, were higher in the male transgenic
hearts compared with wild-type, implying a role for
Na+/Ca2+ exchange in the contraction, as well
as the relaxation, phases of the cardiac beat. Postischemic
function was lower in male transgenic than in male wild-type hearts
(7±2% versus 32±6% of preischemic function), but there
was no difference between female transgenic and female wild-type
hearts, both at 
30% of preischemic function. To assess
whether this male/female difference was due to female-specific hormones
such as estrogen, the hearts of bilaterally ovariectomized and
sham-operated transgenic females were subjected to the same protocol.
The functional recoveries of ovariectomized female transgenic hearts
were lower (17±3% of preischemic function) than those of
wild-type and sham-operated transgenic females. The lower
postischemic functional recovery in the male transgenic and
female ovariectomized transgenic hearts correlated with lower
recoveries of the energy metabolites, ATP and phosphocreatine, as
measured by 31P nuclear magnetic resonance spectroscopy.
Alternans were observed during reperfusion in male transgenic and
female ovariectomized transgenic hearts only, consistent with
intracellular Ca2+ overload. Western analyses
showed that alterations in the expression of the
Na+/Ca2+ exchange or L-type Ca2+
channel proteins were not responsible for the protection observed in
the female transgenic hearts. In conclusion, in males, overexpression
of the Na+/Ca2+ exchanger reduced
postischemic recovery of both contractile function and
energy metabolites, indicating that the
Na+/Ca2+ exchanger may play a role in
ischemia/reperfusion injury. From the studies of females,
however, it appears that this exacerbation of
ischemia/reperfusion injury by overexpression of the
Na+/Ca2+ exchanger can be overcome partially by
female-specific hormones such as estrogen.
Key Words: alternans • estrogen • ischemia • Na+/Ca2+ exchange • protein expression
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