Assiciations of Hypertension and Its Complications with Variations in the Xanthine Dehydrogenase Gene

Yang, Jin; Kamide, Kei; Kokubo, Yoshihiro; Takiuchi, Shin; Horio, Takeshi; Matayoshi, Tetsutaro; Yasuda, Hisayo; Miwa, Yoshiro; Yoshii, Masayoshi; Yoshihara, Fumiki; Nakamura, Satoko; Nakahama, Hajime; Tomoike, Hitonobu; Miyata, Toshiyuki; Kawano, Yuhei

doi:10.1291/hypres.31.931

Cited by 40 publications

(28 citation statements)

References 54 publications

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“…We were also interested in validating the transcriptional profiles of genes engaged in guanine, inosine and hypoxanthine degradation pathways, such as Gda (Guanine deaminase), Pnp (Purine nucleoside phosphorylase) and Xdh (Xanthine dehydrogenase) [32,33]. We found that all transcripts that are involved in these pathways were unaltered in the hearts of HD mouse models (Fig.…”

Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 99%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

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Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 99%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…If true, this might also explain the lack of association, as a polymorphism that would increase serum levels would paradoxically reduce intracellular levels. Indeed, there is evidence that polymorphisms of XOR associated with increased activity are associated with hypertension [104,105].…”

Section: Limitations and Controversiesmentioning

confidence: 99%

Uric Acid and Hypertension: Cause or Effect?

et al. 2010

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Uric acid was first associated with primary hypertension in 1874, yet its role in this condition remains unclear. Historically, uric acid was thought to be a secondary response to hypertension or its associated conditions. However, more recent experimental and clinical studies suggest that uric acid could have a contributory role in the pathogenesis of elevated blood pressure. More studies are needed to help dissect the potential mechanisms by which uric acid could initiate this response. It remains possible that uric acid is a marker for xanthine oxidase-associated oxidants and that the latter could be driving the hypertensive response. However, the weight of the evidence suggests that uric acid is a true modifying and possibly causal factor for human primary hypertension. Hence, early management of hyperuricemia might delay the development of essential hypertension.

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“…However, these studies were either small or methodologically suboptimal to form the basis for treatment recommendations and the need of performing such a large trial in adults is perceived as a public health priority in the quest to prevent hypertension by intervening on this metabolic risk factor. Genetic variations in the enzyme that regulates the synthesis of uric acid have already been associated to hypertension, atherosclerosis and chronic kidney disease in a community study in Japan [18].…”

Section: Discussionmentioning

confidence: 99%

A polymorphism in the major gene regulating serum uric acid associates with clinic SBP and the white-coat effect in a family-based study

Mallamaci¹,

Testa²,

Leonardis³

et al. 2014

Journal of Hypertension

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Assiciations of Hypertension and Its Complications with Variations in the Xanthine Dehydrogenase Gene

Cited by 40 publications

References 54 publications

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Uric Acid and Hypertension: Cause or Effect?

A polymorphism in the major gene regulating serum uric acid associates with clinic SBP and the white-coat effect in a family-based study

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