Chronic allopurinol administration ameliorates maladaptive alterations in Ca 2+ cycling proteins and β-adrenergic hyporesponsiveness in heart failure

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 Ca 2+ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothes...

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Published in:American journal of physiology. Heart and circulatory physiology 2007-03, Vol.292 (3), p.H1328-H1335
Main Authors: 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.
Format: Article
Language:English
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Summary: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 Ca 2+ 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/d t max ), lusitropic (τ), and vascular (elastance; E a ) 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 + /Ca 2+ 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 Ca 2+ 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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00461.2006