Diminished alpha(1)-adrenergic-mediated contraction and translocation of PKC in senescent rat heart

Citation
Dh. Korzick et al., Diminished alpha(1)-adrenergic-mediated contraction and translocation of PKC in senescent rat heart, AM J P-HEAR, 281(2), 2001, pp. H581-H589
Citations number
52
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
ISSN journal
0363-6135 → ACNP
Volume
281
Issue
2
Year of publication
2001
Pages
H581 - H589
Database
ISI
SICI code
0363-6135(200108)281:2<H581:DACATO>2.0.ZU;2-I
Abstract
Myocardial reserve function declines with aging due in part to reduced alph a- and beta -adrenergic receptor (AR)-mediated contractile augmentation. Wh ereas specific age-associated deficits in beta -AR signaling have been iden tified, it is not known which components of the alpha (1)-AR signaling casc ade, e.g., protein kinase C (PKC) and associated anchoring proteins (recept ors for activated C kinase; RACKs), underlie deficits in alpha (1)-AR contr actile function with aging. We therefore assessed cardiac contraction (dP/d t) in Langendorff perfused hearts isolated from adult (5 mo) and senescent (24 mo) Wistar rats following maximal alpha (1)-AR stimulation with phenyle phrine (PE), and we measured the subcellular distribution of PKC alpha and PKC epsilon, and their respective anchoring proteins RACK1 and RACK2 by Wes tern blotting. The maximum dP/dt response to PE (10(-5) M) was significantl y reduced by 41% in 24-mo-old vs. 5-mo-old (P < 0.01). Inhibitory effects o f PKC blockade (chelerythrine; 10 <mu>M) on dP/dt following alpha (1)-AR st imulation 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<alpha > and PKC epsilon levels, while increasing particulate PKC alpha and PKC ep silon levels to a similar extent. In contrast, soluble PKC alpha and PKC ep silon levels in 24-mo-old hearts were increased in response to PE; particul ate PKC epsilon and PKC alpha were unchanged or reduced and associated with significant reductions in particulate RACK1 and RACK2. The results indicat e, for the first time, that selective translocation of PKC alpha and PKC ep silon in response to alpha (1)-AR stimulation is disrupted in the senescent myocardium. That age-related reductions in particulate RACK1 and RACK2 lev els were also observed provide evidence that alterations in PKC-anchoring p roteins may contribute to impaired PKC translocation and defective alpha (1 )-AR contraction in the aged rat heart.