Diminished α1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart

D. H. Korzick, D. A. Holiman, M. O. Boluyt, M. H. Laughlin, Edward Lakatta

Research output: Contribution to journalArticle

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 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 languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume281
Issue number2 50-2
StatePublished - 2001
Externally publishedYes

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

Keywords

  • Aging
  • Cell surface receptors
  • Myocardium
  • Receptors for activated C kinase
  • Signal transduction

ASJC Scopus subject areas

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

Cite this

Diminished α1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart. / Korzick, D. H.; Holiman, D. A.; Boluyt, M. O.; Laughlin, M. H.; Lakatta, Edward.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 281, No. 2 50-2, 2001.

Research output: Contribution to journalArticle

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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 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.",
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T1 - Diminished α1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart

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AU - Holiman, D. A.

AU - Boluyt, M. O.

AU - Laughlin, M. H.

AU - Lakatta, Edward

PY - 2001

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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 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.

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