Myocardial reserve function declines with aging due in part to reduced α- and β-adrenergic receptor (AR)-mediated contractile augmentation. Whereas specific age-associated deficits in β-AR signaling have been identified, it is not known which components of the α1-AR signaling cascade, e.g., protein kinase C (PKC) and associated anchoring proteins (receptors for activated C kinase; RACKs), underlie deficits in α1-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 α1-AR stimulation with phenylephrine (PE), and we measured the subcellular distribution of PKCα and PKCε, 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 α1-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 PKCα and PKCε levels, while increasing particulate PKCα and PKCε levels to a similar extent. In contrast, soluble PKCα and PKCε levels in 24-mo-old hearts were increased in response to PE; particulate PKCε and PKCα 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 PKCα and PKCε in response to α1-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 α1-AR contraction in the aged rat heart.
|Original language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Issue number||2 50-2|
|State||Published - Aug 29 2001|
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- Physiology (medical)