© 1997 American Heart Association, Inc.
Articles |
Ca2+ as a Mediator of Ischemic Preconditioning
From the Department of Pathology and Laboratory Medicine, University of Cincinnati (Ohio) Medical Center.
Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0529.
Abstract We tested the hypothesis that elevation of
[Ca2+]i during ischemic
preconditioning (IPC) stimulates protein kinase C (PKC), which confers
the protection against the ischemic injury.
Langendorff-perfused rat hearts were subjected to 40-minute global
ischemia followed by 30-minute reperfusion (I/R). In
preconditioned groups, hearts were subjected to either IPC, consisting
of 5-minute global ischemia and 10-minute reperfusion, or
high-Ca2+ preconditioning (HCPC), ie, the 5-minute
perfusion of higher Ca2+ perfusate (2.3 mmol/L
Ca2+) followed by 10-minute perfusion of normal
perfusate (1.8 mmol/L Ca2+), and then were
subjected to I/R. A significant functional recovery and decreased
lactate dehydrogenase release were observed in HCPC and IPC hearts
compared with ischemic control hearts. ATP contents of
preconditioned hearts were significantly higher than those of the
ischemic control hearts. The cell structure in preconditioned
hearts was preserved better than that in the ischemic control
hearts. Furthermore, the activation and translocation of PKC from
cytoplasm to sarcolemma were observed in the preconditioned hearts.
Verapamil administered during IPC significantly attenuated
the salutary effects of IPC. Administration of chelerythrine, a
specific PKC inhibitor, completely abolished the HCPC- and
IPC-induced cardioprotection. The translocation of PKC by IPC was
blocked by verapamil or chelerythrine. Immunohistochemical
study using rabbit polyclonal antibody against PKC isoforms indicated
that stress induced by IPC or HCPC evoked the translocation of PKC
and PKC
to the cell membrane. Translocation of PKC isoforms was
attenuated by the treatment with verapamil or
chelerythrine. These results demonstrate that (1) a transient increase
in [Ca2+]i during IPC is an important trigger
for the activation of PKC, which is responsible for cardioprotection;
(2) the elevation of [Ca2+]i during IPC, at
least partly, resulted from Ca2+ entry via
voltage-dependent Ca2+ channel; and (3) activation and
translocation of PKC and PKC occur during IPC and HCPC and may be
important in preconditioning.
Key Words: preconditioning • ischemia • intracellular Ca2+ • protein kinase C
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