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1-adrenergic-mediated
contraction and translocation of PKC in senescent rat
heart
1 Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, Missouri 65211; and 2 Laboratory of Cardiovascular Science, The National Institute on Aging, Baltimore, Maryland 21224
Myocardial reserve
function declines with aging due in part to reduced 
- and
-adrenergic receptor (AR)-mediated contractile augmentation. Whereas
specific age-associated deficits in -AR signaling have been
identified, it is not known which components of the 1-AR
signaling cascade, e.g., protein kinase C (PKC) and associated
anchoring proteins (receptors for activated C kinase; RACKs), underlie
deficits in 1-AR contractile function with aging. We
therefore assessed cardiac contraction (dP/dt) in
Langendorff perfused hearts isolated from adult (5 mo) and senescent
(24 mo) Wistar rats following maximal 1-AR stimulation
with phenylephrine (PE), and we measured the subcellular distribution
of PKC and PKC
, and their respective anchoring proteins RACK1 and
RACK2 by Western blotting. The maximum dP/dt response to PE
(10
5 M) was significantly reduced by 41% in 24-mo-old
vs. 5-mo-old (P < 0.01). Inhibitory effects of PKC
blockade (chelerythrine; 10 µM) on dP/dt following
1-AR stimulation with PE observed in adult hearts were
absent in 24-mo-old hearts (P < 0.01). In 5-mo-old hearts, PE elicited reductions in soluble PKC and PKC
levels, while increasing particulate PKC and PKC levels to a
similar extent. In contrast, soluble PKC and PKC levels
in 24-mo-old hearts were increased in response to PE; particulate
PKC and PKC were unchanged or reduced and associated with
significant reductions in particulate RACK1 and RACK2. The results
indicate, for the first time, that selective translocation of PKC
and PKC in response to 1-AR stimulation is disrupted
in the senescent myocardium. That age-related reductions in particulate
RACK1 and RACK2 levels were also observed provide evidence that
alterations in PKC-anchoring proteins may contribute to impaired PKC
translocation and defective 1-AR contraction in the aged
rat heart.
myocardium; signal transduction; cell surface receptors; aging; receptors for activated C kinase
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