Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy

Khalid M. Minhas, Roberto M. Saraiva, Karl H. Schuleri, Stephanie Lehrke, Meizi Zheng, Anastasios P. Saliaris, Cristine E Berry, Konrad M. Vandegaer, Dechun Li, Joshua M. Hare

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31±3% versus 67±3% in WKY, P<0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7±0.2 mm versus 7.0±0.4 mm in WKY, P<0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho-extracellular signal-regulated kinase were restored toward normal by oxypurinol (P<0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.

Original languageEnglish (US)
Pages (from-to)271-279
Number of pages9
JournalCirculation Research
Volume98
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Fingerprint

Oxypurinol
Xanthine Dehydrogenase
Dilated Cardiomyopathy
Inbred SHR Rats
Heart Failure
Placebos
Reactive Oxygen Species
NADPH Oxidase
Extracellular Signal-Regulated MAP Kinases
Protein Subunits
Superoxides
Muscle Cells
Transcriptional Activation
Oxidative Stress
Calcium
Phenotype
Gene Expression
Messenger RNA

Keywords

  • Gene expression
  • Heart failure
  • Remodeling
  • Xanthine oxidoreductase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Minhas, K. M., Saraiva, R. M., Schuleri, K. H., Lehrke, S., Zheng, M., Saliaris, A. P., ... Hare, J. M. (2006). Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. Circulation Research, 98(2), 271-279. https://doi.org/10.1161/01.RES.0000200181.59551.71

Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. / Minhas, Khalid M.; Saraiva, Roberto M.; Schuleri, Karl H.; Lehrke, Stephanie; Zheng, Meizi; Saliaris, Anastasios P.; Berry, Cristine E; Vandegaer, Konrad M.; Li, Dechun; Hare, Joshua M.

In: Circulation Research, Vol. 98, No. 2, 02.2006, p. 271-279.

Research output: Contribution to journalArticle

Minhas, KM, Saraiva, RM, Schuleri, KH, Lehrke, S, Zheng, M, Saliaris, AP, Berry, CE, Vandegaer, KM, Li, D & Hare, JM 2006, 'Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy', Circulation Research, vol. 98, no. 2, pp. 271-279. https://doi.org/10.1161/01.RES.0000200181.59551.71
Minhas, Khalid M. ; Saraiva, Roberto M. ; Schuleri, Karl H. ; Lehrke, Stephanie ; Zheng, Meizi ; Saliaris, Anastasios P. ; Berry, Cristine E ; Vandegaer, Konrad M. ; Li, Dechun ; Hare, Joshua M. / Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. In: Circulation Research. 2006 ; Vol. 98, No. 2. pp. 271-279.
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