© 1999 American Heart Association, Inc.
Integrative Physiology |
Diminished Basal Phosphorylation Level of Phospholamban in the Postinfarction Remodeled Rat Ventricle
Role of ß-Adrenergic Pathway, Gi Protein, Phosphodiesterase, and Phosphatases
From the Cardiology Division (B.H., D.Q., M.B., N.E.-S.), Department of Medicine, State University of New York Health Science Center and Veterans Affairs Medical Center, Brooklyn, NY, and Laboratory of Cardiovascular Science (S.W.), Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Md.
Correspondence to Nabil El-Sherif, Cardiology Division, Box 1199, SUNY Health Science Center, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail nelsherif{at}aol.com
Abstract—Three weeks after
myocardial infarction (MI) in the rat, remodeled
hypertrophy of noninfarcted myocardium is at
its maximum and the heart is in a compensated stage with no evidence of
heart failure. Our hemodynamic measurements at this
stage showed a slight but insignificant decrease of +dP/dt but a
significantly higher left ventricular
end-diastolic pressure. To investigate the basis of the
diastolic dysfunction, we explored possible defects in the
ß-adrenergic receptor–Gs/i protein–adenylyl
cyclase–cAMP–protein kinase A–phosphatase pathway, as well as
molecular or functional alterations of sarcoplasmic reticulum
Ca2+-ATPase and phospholamban (PLB). We found no
significant difference in both mRNA and protein levels of sarcoplasmic
reticulum Ca2+-ATPase and PLB in post-MI left ventricle
compared with control. However, the basal levels of both the protein
kinase A–phosphorylated site (Ser16) of PLB (p16-PLB)
and the calcium/calmodulin–dependent protein
kinase-phosphorylated site (Thr17) of PLB (p17-PLB)
were decreased by 76% and 51% in post-MI myocytes
(P<0.05), respectively. No change was found in the
ß-adrenoceptor density, Gs
protein level, or adenylyl
cyclase activity. Inhibition of phosphodiesterase and Gi
protein by Ro-20-1724 and pertussis toxin, respectively, did not
correct the decreased p16-PLB or p17-PLB levels. Stimulation of
ß-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB
in post-MI myocytes to the same levels as in sham myocytes, suggesting
that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a
decrease in the generation of p16-PLB or p17-PLB. We found that type 1
phosphatase activity was increased by 32% (P<0.05)
with no change in phosphatase 2A activity. Okadaic acid, a protein
phosphatase inhibitor, significantly increased p16-PLB and
p17-PLB levels in post-MI myocytes and partially corrected the
prolonged relaxation of the [Ca2+]i
transient. In summary, prolonged relaxation of post-MI remodeled
myocardium could be explained, in part, by altered basal
levels of p16-PLB and p17-PLB caused by increased protein phosphatase
1 activity.
Key Words: phospholamban • phosphatase • postmyocardial infarction • sarcoplasmic reticulum
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