E-NTPDases and ecto-5′-nucleotidase expression profile in rat heart left ventricle and the extracellular nucleotide hydrolysis by their nerve terminal endings

Rücker, Bárbara; Almeida, Manoela Enger; Libermann, Towia A.; Zerbini, Luiz F.; Wink, Márcia Rosângela; Sarkis, João José Freitas

doi:10.1016/j.lfs.2007.12.003

Cited by 26 publications

(15 citation statements)

References 63 publications

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“…The next protocol was performed to assess E-NTPDase activity in aortic homogenate preparations in the presence or absence of Gd. Several studies have reported the ability of Gd to decrease nucleotide hydrolysis (6,22,23). In the present study, we observed that Gd was capable of inhibiting both ATP and ADP hydrolysis.…”

Section: Discussionsupporting

confidence: 65%

Gadolinium increases the vascular reactivity of rat aortic rings

Angeli

Ramos

Casali

et al. 2011

Braz J Med Biol Res

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Section: Discussionsupporting

confidence: 65%

Gadolinium increases the vascular reactivity of rat aortic rings

Angeli

Ramos

Casali

et al. 2011

Braz J Med Biol Res

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“…Altered transcripts of genes responsible for ATP degradation, such as Entpd2 (Ectonucleoside triphosphate diphosphohydrolase 2) and Nme3 (Nucleoside diphosphate kinase 3), were observed in the HdhQ150 mouse model and could interfere with regulation of the ATP pool. Entpd2 has been identified as a key enzyme with a role in regulating nucleotide-mediated signaling, and in controlling the rate, amount and timing of nucleotide degradation [62]. It is well-established that nucleoside diphosphate kinase possesses a histidine kinase activity for G-beta proteins that could potentially contribute to receptor-independent regulation of cAMP synthesis and the contractility of cardiomyocytes [63].…”

Section: Discussionmentioning

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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“…Another myocardium-specific upregulated gene is Endtp2. Entdp2 is the isoform with the highest expression in the rat left ventricle (28). Entdp enzymes convert extracellular ATP and ADP to AMP and, thus, reduce P2 receptor activation.…”

Section: Discussionmentioning

confidence: 99%

G_i proteins mediate activation of the canonical hedgehog pathway in the myocardium

Carbe

Cheng

Addya

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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During myocardial ischemia, upregulation of the hedgehog (Hh) pathway promotes neovascularization and increases cardiomyocyte survival. The canonical Hh pathway activates a transcriptional program through the Gli family of transcription factors by derepression of the seven-transmembrane protein smoothened (Smo). The mechanisms linking Smo to Gli are complex and, in some cell types, involve coupling of Smo to Gi proteins. In the present study, we investigated, for the first time, the transcriptional response of cardiomyocytes to sonic hedgehog (Shh) and the role of Gi protein utilization. Our results show that Shh strongly activates Gli1 expression by quantitative PCR in a Smo-dependent manner in neonatal rat ventricular cardiomyocytes. Microarray analysis of gene expression changes elicited by Shh and sensitive to a Smo inhibitor identified a small subset of 37 cardiomyocyte-specific genes regulated by Shh, including some in the PKA and purinergic signaling pathways. In addition, neonatal rat ventricular cardiomyocytes infected with an adenovirus encoding GiCT, a peptide that impairs receptor-Gi protein coupling, showed reduced activation of Hh targets. In vitro data were confirmed in transgenic mice with cardiomyocyte-inducible GiCT expression. Transgenic GiCT mice showed specific reduction of Gli1 expression in the heart under basal conditions and failed to upregulate the Hh pathway upon ischemia and reperfusion injury, unlike their littermate controls. This study characterizes, for the first time, the transcriptional response of cardiomyocytes to Shh and establishes a critical role for Smo coupling to Gi in Hh signaling in the normal and ischemic myocardium.

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E-NTPDases and ecto-5′-nucleotidase expression profile in rat heart left ventricle and the extracellular nucleotide hydrolysis by their nerve terminal endings

Cited by 26 publications

References 63 publications

Gadolinium increases the vascular reactivity of rat aortic rings

Gadolinium increases the vascular reactivity of rat aortic rings

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

G_i proteins mediate activation of the canonical hedgehog pathway in the myocardium

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E-NTPDases and ecto-5′-nucleotidase expression profile in rat heart left ventricle and the extracellular nucleotide hydrolysis by their nerve terminal endings

Cited by 26 publications

References 63 publications

Gadolinium increases the vascular reactivity of rat aortic rings

Gadolinium increases the vascular reactivity of rat aortic rings

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

Gi proteins mediate activation of the canonical hedgehog pathway in the myocardium

Contact Info

Product

Resources

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G_i proteins mediate activation of the canonical hedgehog pathway in the myocardium