Diminished α 1 -adrenergic-mediated contraction and translocation of PKC in senescent rat heart

Donna Hope Korzick, D. A. Holiman, M. O. Boluyt, M. H. Laughlin, E. G. Lakatta

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Abstract

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 α 1 -AR signaling cascade, e.g., protein kinase C (PKC) and associated anchoring proteins (receptors for activated C kinase; RACKs), underlie deficits in α 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 α 1 -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 α 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 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 α 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 α 1 -AR contraction in the aged rat heart.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume281
Issue number2 50-2
StatePublished - Aug 29 2001

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Adrenergic Agents
Protein Kinase C
Adrenergic Receptors
Phenylephrine
Proteins
protein kinase C kinase
Wistar Rats
Myocardium
Western Blotting

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{27f39feeaee94240b8498956370bace3,
title = "Diminished α 1 -adrenergic-mediated contraction and translocation of PKC in senescent rat heart",
abstract = "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 α 1 -AR signaling cascade, e.g., protein kinase C (PKC) and associated anchoring proteins (receptors for activated C kinase; RACKs), underlie deficits in α 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 α 1 -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 α 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 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 α 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 α 1 -AR contraction in the aged rat heart.",
author = "Korzick, {Donna Hope} and Holiman, {D. A.} and Boluyt, {M. O.} and Laughlin, {M. H.} and Lakatta, {E. G.}",
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Diminished α 1 -adrenergic-mediated contraction and translocation of PKC in senescent rat heart . / Korzick, Donna Hope; Holiman, D. A.; Boluyt, M. O.; Laughlin, M. H.; Lakatta, E. G.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 281, No. 2 50-2, 29.08.2001.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Diminished α 1 -adrenergic-mediated contraction and translocation of PKC in senescent rat heart

AU - Korzick, Donna Hope

AU - Holiman, D. A.

AU - Boluyt, M. O.

AU - Laughlin, M. H.

AU - Lakatta, E. G.

PY - 2001/8/29

Y1 - 2001/8/29

N2 - 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 α 1 -AR signaling cascade, e.g., protein kinase C (PKC) and associated anchoring proteins (receptors for activated C kinase; RACKs), underlie deficits in α 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 α 1 -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 α 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 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 α 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 α 1 -AR contraction in the aged rat heart.

AB - 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 α 1 -AR signaling cascade, e.g., protein kinase C (PKC) and associated anchoring proteins (receptors for activated C kinase; RACKs), underlie deficits in α 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 α 1 -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 α 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 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 α 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 α 1 -AR contraction in the aged rat heart.

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