Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and β-adrenergic hyporesponsiveness in heart failure

Anastasios P. Saliaris, Luciano C. Amado, Khalid M. Minhas, Karl H. Schuleri, Stephanie Lehrke, Marcus St. John, Torin Fitton, Chris Barreiro, Cristine Berry, Meizi Zheng, Kristen Kozielski, Virginia Eneboe, Jeff Brawn, Joshua M. Hare

Research output: Contribution to journalArticle

Abstract

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). β-Adrenergic hyporesponsiveness and abnormalities in Ca2+ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences β-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dtmax), lusitropic (τ), and vascular (elastance; Ea) responses to β-adrenergic (β-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca 2+-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na+/Ca2+ transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P <0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca2+ cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and β-adrenergic hyporesponsiveness.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number3
DOIs
StatePublished - Mar 2007

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Allopurinol
Adrenergic Agents
Heart Failure
Dobutamine
Xanthine Oxidase
Proteins
Excitation Contraction Coupling
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Phenotype
Gene Expression
Vasoconstrictor Agents
Cyclic AMP-Dependent Protein Kinases
Vasodilator Agents
Oxidants
Blood Vessels
Placebos
Dogs
Messenger RNA
phospholamban

Keywords

  • Calcium signaling
  • Cardiac contractility and energetics
  • Excitation-contraction coupling
  • Oxidative stress
  • Xanthine oxidase

ASJC Scopus subject areas

  • Physiology

Cite this

Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and β-adrenergic hyporesponsiveness in heart failure. / Saliaris, Anastasios P.; Amado, Luciano C.; Minhas, Khalid M.; Schuleri, Karl H.; Lehrke, Stephanie; St. John, Marcus; Fitton, Torin; Barreiro, Chris; Berry, Cristine; Zheng, Meizi; Kozielski, Kristen; Eneboe, Virginia; Brawn, Jeff; Hare, Joshua M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 292, No. 3, 03.2007.

Research output: Contribution to journalArticle

Saliaris, AP, Amado, LC, Minhas, KM, Schuleri, KH, Lehrke, S, St. John, M, Fitton, T, Barreiro, C, Berry, C, Zheng, M, Kozielski, K, Eneboe, V, Brawn, J & Hare, JM 2007, 'Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and β-adrenergic hyporesponsiveness in heart failure', American Journal of Physiology - Heart and Circulatory Physiology, vol. 292, no. 3. https://doi.org/10.1152/ajpheart.00461.2006
Saliaris, Anastasios P. ; Amado, Luciano C. ; Minhas, Khalid M. ; Schuleri, Karl H. ; Lehrke, Stephanie ; St. John, Marcus ; Fitton, Torin ; Barreiro, Chris ; Berry, Cristine ; Zheng, Meizi ; Kozielski, Kristen ; Eneboe, Virginia ; Brawn, Jeff ; Hare, Joshua M. / Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and β-adrenergic hyporesponsiveness in heart failure. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 292, No. 3.
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abstract = "Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). β-Adrenergic hyporesponsiveness and abnormalities in Ca2+ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences β-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dtmax), lusitropic (τ), and vascular (elastance; Ea) responses to β-adrenergic (β-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca 2+-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na+/Ca2+ transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P <0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca2+ cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and β-adrenergic hyporesponsiveness.",
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AU - Amado, Luciano C.

AU - Minhas, Khalid M.

AU - Schuleri, Karl H.

AU - Lehrke, Stephanie

AU - St. John, Marcus

AU - Fitton, Torin

AU - Barreiro, Chris

AU - Berry, Cristine

AU - Zheng, Meizi

AU - Kozielski, Kristen

AU - Eneboe, Virginia

AU - Brawn, Jeff

AU - Hare, Joshua M.

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N2 - Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). β-Adrenergic hyporesponsiveness and abnormalities in Ca2+ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences β-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dtmax), lusitropic (τ), and vascular (elastance; Ea) responses to β-adrenergic (β-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca 2+-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na+/Ca2+ transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P <0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca2+ cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and β-adrenergic hyporesponsiveness.

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