Uridine triphosphate (UTP) is released during cardiac ischemia

Erlinge, David; Harnek, Jan; Heusden, Catharina van; Olivecrona, Göran; Jern, Sverker; Lazarowski, Eduardo R.

doi:10.1016/j.ijcard.2004.10.005

Cited by 45 publications

(34 citation statements)

References 23 publications

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“…However, the monocyte-chemoattracting activity of CM-PA was abolished by apyrase, and we corroborated that apyrase cleaves all nucleotide triphosphates. While the vast majority of studies on physiologically released nucleotides have focused on ATP, UTP is also released during cardiac ischemia (47) and is a potent inducer of cell migration (48). Since cytidine triphosphate, GTP, and TTP could not be detected in CM-PA (assayed with a detection limit of 2 nmol/L), and .1 mmol/L each is required for effective chemoattraction (Fig.…”

Section: Discussionmentioning

confidence: 99%

Nucleotides Released From Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes

Pillon

Fink

et al. 2014

Diabetes

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Obesity-associated low-grade inflammation in metabolically relevant tissues contributes to insulin resistance. We recently reported monocyte/macrophage infiltration in mouse and human skeletal muscles. However, the molecular triggers of this infiltration are unknown, and the role of muscle cells in this context is poorly understood. Animal studies are not amenable to the specific investigation of this vectorial cellular communication. Using cell cultures, we investigated the crosstalk between myotubes and monocytes exposed to physiological levels of saturated and unsaturated fatty acids. Media from L6 myotubes treated with palmitate—but not palmitoleate—induced THP1 monocyte migration across transwells. Palmitate activated the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in myotubes and elevated cytokine expression, but the monocyte chemoattracting agent was not a polypeptide. Instead, nucleotide degradation eliminated the chemoattracting properties of the myotube-conditioned media. Moreover, palmitate-induced expression and activity of pannexin-3 channels in myotubes were mediated by TLR4-NF-κB, and TLR4-NF-κB inhibition or pannexin-3 knockdown prevented monocyte chemoattraction. In mice, the expression of pannexin channels increased in adipose tissue and skeletal muscle in response to high-fat feeding. These findings identify pannexins as new targets of saturated fatty acid–induced inflammation in myotubes, and point to nucleotides as possible mediators of immune cell chemoattraction toward muscle in the context of obesity.

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Section: Discussionmentioning

confidence: 99%

Nucleotides Released From Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes

Pillon

Fink

et al. 2014

Diabetes

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“…However, we recently performed animal studies in which the release was measured in blood from the cardiac vein, demonstrating UTP release from the heart during cardiac ischemia. 9 UTP is therefore likely to be released from the heart by cardiomyocytes, but endothelial and red blood cells may also contribute. Platelets are less likely as a source because they contain minor amounts of UTP.…”

Section: Discussionmentioning

confidence: 99%

“…Measuring UTP release from the heart during cardiac ischemia the nucleotide concentrations in plasma are in 10 Ϫ7 mol/L range. 9 In this experiment we therefore choose the concentration of 10 Ϫ6 mol/L, that may represent a physiologically relevant concentration.…”

Section: Discussionmentioning

confidence: 99%

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Positive Inotropic Effects by Uridine Triphosphate (UTP) and Uridine Diphosphate (UDP) via P2Y ₂ and P2Y ₆ Receptors on Cardiomyocytes and Release of UTP in Man During Myocardial Infarction

Wihlborg

Balogh

Wang

et al. 2006

Circulation Research

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110

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Abstract-The aim of this study was to examine a possible role for extracellular pyrimidines as inotropic factors for the heart. First, nucleotide plasma levels were measured to evaluate whether UTP is released in patients with coronary heart disease. Then, inotropic effects of pyrimidines were examined in isolated mouse cardiomyocytes. Finally, expression of pyrimidine-selective receptors (a subgroup of the P2 receptors) was studied in human and mouse heart, using real time polymerase chain reaction, Western blot, and immunohistochemistry. Venous plasma levels of UTP were increased (57%) in patients with myocardial infarction. In electrically stimulated cardiomyocytes the stable P2Y 2/4 agonist UTP␥S increased contraction by 52%, similar to ␤ 1 -adrenergic stimulation with isoproterenol (65%). The P2Y 6 -agonist UDP␤S also increased cardiomyocyte contraction (35%), an effect abolished by the P2Y 6 -blocker MRS2578. The phospholipase C inhibitor U73122 inhibited both the UDP␤S and the UTP␥S-induced inotropic effect, indicating an IP 3 -mediated effect via P2Y 6 receptors. The P2Y 14 agonist UDP-glucose was without effect. Quantification of mRNA with real time polymerase chain reaction revealed P2Y 2 as the most abundant pyrimidine receptor expressed in cardiomyocytes from man. Presence of P2Y 6 receptor mRNA was detected in both species and confirmed at protein level with Western blot and immunohistochemistry in man. In conclusion, UTP levels are increased in humans during myocardial infarction, giving the first evidence for UTP release in man. UTP is a cardiac inotropic factor most likely by activation of P2Y 2 receptors in man.

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“…DAG activates protein kinase C (PKC) and mitogen-activated protein kinases [19]. Whereas the effects of purine nucleosides and nucleotides in myocardial infarction and ischemia have been intensively studied [2,20], the role of pyrimidine nucleotides under hypoxic conditions has not been well explored [18], although the level of both ATP and UTP were found to be elevated as a result of ischemia [7]. Using rat cell culture we found that UTP protected cardiomyocytes from hypoxic damage through the activation of P2Y 2 receptors [26].…”

Section: Introductionmentioning

confidence: 99%

Uridine-5′-triphosphate (UTP) reduces infarct size and improves rat heart function after myocardial infarct

Yitzhaki

Shainberg

Cheporko

et al. 2006

Biochemical Pharmacology

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We have previously found that uridine 5′-triphosphate (UTP) significantly reduced cardiomyocyte death induced by hypoxia via activating P2Y 2 receptors. To explore the effect of UTP following myocardial infarction (MI) in vivo we studied four groups: sham with or without LAD ligation, injected with UTP (0.44 µg/kg i.v.) 30 min before MI, and UTP injection (4.4 µg/kg i.v.) 24 h prior to MI. Left ventricular end diastolic area (LVEDA), end systolic area (LVESA) fractional shortening (FS), and changes in posterior wall (PW) thickness were performed by echocardiography before and 24 h after MI. In addition, we measured different biochemical markers of damage and infarct size using Evans blue and TTC staining. The increase in LVEDA and LVESA of the treated animals was significantly smaller when compared to the MI rats (p < 0.01). Concomitantly, FS was higher in groups pretreated with UTP 30 min or 24 h (56 ± 14.3 and 36.7 ± 8.2%, p < 0.01, respectively). Ratio of infarct size to area at risk was smaller in the UTP pretreated hearts than MI rats (22.9 ± 6.6, 23.1 ± 9.1%, versus 45.4 ± 7.6%, respectively, p < 0.001). Troponin T and ATP measurements, demonstrated reduced myocardial damage. Using Rhod-2-AM loaded cardiomyocytes, we found that UTP reduced mitochondrial calcium levels following hypoxia. In conclusion, early or late UTP preconditioning is effective, demonstrating reduced infarct size and superior myocardial function. The resulting cardioprotection following UTP treatment post ischemia demonstrates a reduction in mitochondrial calcium overload, which can explain the beneficial effect of UTP.

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Uridine triphosphate (UTP) is released during cardiac ischemia

Cited by 45 publications

References 23 publications

Nucleotides Released From Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes

Nucleotides Released From Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes

Positive Inotropic Effects by Uridine Triphosphate (UTP) and Uridine Diphosphate (UDP) via P2Y ₂ and P2Y ₆ Receptors on Cardiomyocytes and Release of UTP in Man During Myocardial Infarction

Uridine-5′-triphosphate (UTP) reduces infarct size and improves rat heart function after myocardial infarct

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Uridine triphosphate (UTP) is released during cardiac ischemia

Cited by 45 publications

References 23 publications

Nucleotides Released From Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes

Nucleotides Released From Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes

Positive Inotropic Effects by Uridine Triphosphate (UTP) and Uridine Diphosphate (UDP) via P2Y 2 and P2Y 6 Receptors on Cardiomyocytes and Release of UTP in Man During Myocardial Infarction

Uridine-5′-triphosphate (UTP) reduces infarct size and improves rat heart function after myocardial infarct

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Product

Resources

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Positive Inotropic Effects by Uridine Triphosphate (UTP) and Uridine Diphosphate (UDP) via P2Y ₂ and P2Y ₆ Receptors on Cardiomyocytes and Release of UTP in Man During Myocardial Infarction