Pyruvate restores β-adrenergic sensitivity of L-type Ca2+ channels in failing rat heart: Role of protein phosphatase

Ming Qi Zheng, Xun Li, Kang Tang, Neeru M. Sharma, Todd A Wyatt, Kaushik P Patel, Lie Gao, Keshore R Bidasee, George J. Rozanski

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Oxidative stress plays a major role in the pathogenesis of heart failure, where the contractile response to β-adrenergic stimulation is profoundly depressed. This condition involves L-type Ca2+ channels, but the mechanisms underlying their impaired adrenergic regulation are unclear. Thus the present study explored the basis for impaired adrenergic control of Ca2+ channels in a rat infarction model of heart failure. Patch-clamp recordings of L-type Ca2+ current (ICa,L) from ventricular myocytes isolated from infarcted hearts showed a blunted response to intracellular cAMP that was reversed by treatment with exogenous pyruvate. Biochemical studies showed that basal and cAMP-stimulated protein kinase A activities were similar in infarcted and sham-operated hearts, whereas molecular analysis also found that binding of protein kinase A to the α1C subunit of voltage-gated Ca2+ channel isoform 1.2 was not different between groups. By contrast, protein phosphatase 2A (PP2A) activity and binding to α1C were significantly less in infarcted hearts. The PP2A inhibitor okadaic acid markedly increased ICa,L in sham-operated myocytes, but this response was significantly less in myocytes from infarcted hearts. However, pyruvate normalized ICa,L stimulation by okadaic acid, and this effect was blocked by inhibitors of thioredoxin reductase, implicating a functional role for the redox-active thioredoxin system. Our data suggest that blunted β-adrenergic stimulation of ICaL in failing hearts results from hyperphosphorylation of Ca2+ channels secondary to oxidation-induced impairment of PP2A function. We propose that the redox state of Ca2+ channels or PP2A is controlled by the thioredoxin system which plays a key role in Ca2+ channel remodeling of the failing heart.

Original languageEnglish (US)
Pages (from-to)H1352-H1360
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number10
DOIs
StatePublished - Jun 10 2013

Fingerprint

Phosphoprotein Phosphatases
Pyruvic Acid
Adrenergic Agents
Protein Phosphatase 2
Muscle Cells
Okadaic Acid
Thioredoxins
Cyclic AMP-Dependent Protein Kinases
Oxidation-Reduction
Heart Failure
Thioredoxin-Disulfide Reductase
Infarction
Carrier Proteins
Protein Isoforms
Oxidative Stress

Keywords

  • L-type Ca channel
  • PP2a
  • Pyruvate
  • Thioredoxin

ASJC Scopus subject areas

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

Cite this

Pyruvate restores β-adrenergic sensitivity of L-type Ca2+ channels in failing rat heart : Role of protein phosphatase. / Zheng, Ming Qi; Li, Xun; Tang, Kang; Sharma, Neeru M.; Wyatt, Todd A; Patel, Kaushik P; Gao, Lie; Bidasee, Keshore R; Rozanski, George J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 304, No. 10, 10.06.2013, p. H1352-H1360.

Research output: Contribution to journalArticle

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abstract = "Oxidative stress plays a major role in the pathogenesis of heart failure, where the contractile response to β-adrenergic stimulation is profoundly depressed. This condition involves L-type Ca2+ channels, but the mechanisms underlying their impaired adrenergic regulation are unclear. Thus the present study explored the basis for impaired adrenergic control of Ca2+ channels in a rat infarction model of heart failure. Patch-clamp recordings of L-type Ca2+ current (ICa,L) from ventricular myocytes isolated from infarcted hearts showed a blunted response to intracellular cAMP that was reversed by treatment with exogenous pyruvate. Biochemical studies showed that basal and cAMP-stimulated protein kinase A activities were similar in infarcted and sham-operated hearts, whereas molecular analysis also found that binding of protein kinase A to the α1C subunit of voltage-gated Ca2+ channel isoform 1.2 was not different between groups. By contrast, protein phosphatase 2A (PP2A) activity and binding to α1C were significantly less in infarcted hearts. The PP2A inhibitor okadaic acid markedly increased ICa,L in sham-operated myocytes, but this response was significantly less in myocytes from infarcted hearts. However, pyruvate normalized ICa,L stimulation by okadaic acid, and this effect was blocked by inhibitors of thioredoxin reductase, implicating a functional role for the redox-active thioredoxin system. Our data suggest that blunted β-adrenergic stimulation of ICaL in failing hearts results from hyperphosphorylation of Ca2+ channels secondary to oxidation-induced impairment of PP2A function. We propose that the redox state of Ca2+ channels or PP2A is controlled by the thioredoxin system which plays a key role in Ca2+ channel remodeling of the failing heart.",
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AU - Wyatt, Todd A

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AU - Bidasee, Keshore R

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