From the Departments of Physiology (C.W., C.P.B., G.-S.L., J.M.D.),
Medicine (M.V.C.), and Biochemistry and Molecular Biology (A.H.W., R.E.H.),
University of South Alabama College of Medicine, Mobile, and the Department of
Pathology, East Tennessee State University, Johnson City (S.C.A., C.E.G.).
Correspondence to James M. Downey, PhD, Department of Physiology, MSB 3024, University of South Alabama, College of Medicine, Mobile, AL 36688-0002. E-mail jdowney{at}usamail.usouthal.edu
Background—The role of protein
phosphatases (PPs) during ischemic preconditioning in the
rabbit heart was examined.
Methods and Results—Fostriecin, a potent inhibitor of
PP2A, was administered to isolated rabbit hearts starting either 15
minutes before or 10 minutes after the onset of a 30-minute period of
regional ischemia and continuing until the onset of
reperfusion. After 2 hours of reperfusion, infarct size was measured
with triphenyltetrazolium chloride. In a
second study with isolated rabbit cardiomyocytes, the
effect of fostriecin pretreatment was assessed by measuring changes in
cell osmotic fragility during simulated ischemia. PP1 and PP2A
activities of isolated control and ischemically preconditioned
cells were also measured. In a third series of experiments, left
ventricular biopsies of isolated rabbit hearts were
obtained before and at selected times during 60 minutes of global
ischemia, and the tissue was assayed for PP1 and PP2A
activities. In isolated hearts pretreated with fostriecin, only 8% of
the ischemic zone infarcted, significantly less than that in
untreated control hearts (33%; P<0.001) but comparable
to that in ischemically preconditioned hearts (9%;
P<0.001 versus control). Significant protection was
also observed in the hearts treated only after the onset of
ischemia (18% infarction; P<0.05 versus
control). In isolated myocytes, fostriecin also provided protection
comparable to that produced by metabolic preconditioning.
Preconditioning had no apparent effect on the activity of either PP1 or
PP2A in isolated ventricular myocytes or
ventricular tissue obtained from heart biopsies.
Conclusions—Fostriecin, a potent inhibitor of PP2A,
can protect the rabbit heart from infarction even when administered
after the onset of ischemia. But inhibition of either PP1 or
PP2A does not appear to be the mechanism of protection from
ischemic preconditioning.
© 1998 American Heart Association, Inc.
Basic Science Reports
Fostriecin, an Inhibitor of Protein Phosphatase 2A, Limits Myocardial Infarct Size Even When Administered After Onset of Ischemia
Key Words: ischemia • phosphorylation • protein phosphatases • fostriecin
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