UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor

Cohen, Rinat; Shainberg, Asher; Hochhauser, Edith; Cheporko, Yelena; Tobar, Anna; Birk, Einat; Pinhas, Lidya; Leipziger, Jens; Don, Jeremy; Porat, Eyal E.

doi:10.1016/j.bcp.2011.07.094

Cited by 49 publications

(51 citation statements)

References 42 publications

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“…The present study identifies a protection against myocardial infarction in P2Y 4 -null mice. The discrepancy with the previously reported cardioprotective effect of UTP (13)(14)(15) can be explained by cell-specific actions of UTP. The cardioprotective effect of UTP is mediated by P2Y 2 receptors expressed on cardiomyocytes, whereas P2Y 4 is expressed on cardiac endothelial cells but is absent on cardiomyocytes.…”

Section: Discussioncontrasting

confidence: 96%

“…Release of UTP has been observed in human heart during myocardial infarction (28). The involvement of P2Y 2 receptors in UTP-mediated cardioprotection in vivo has been previously demonstrated (13)(14)(15). P2Y 4 , described as a UTP receptor (16), displays a very restricted tissue distribution including heart and lung, and its physiological role has been poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

“…UTP administration to rats reduced infarct size and enhanced myocardial function (14). The implication of P2Y 2 receptor in the cardioprotection mediated in vivo by UTP has been recently demonstrated (15).…”

mentioning

confidence: 96%

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Loss of Mouse P2Y4 Nucleotide Receptor Protects against Myocardial Infarction through Endothelin-1 Downregulation

Horckmans

Esfahani

Beauloye

et al. 2015

The Journal of Immunology

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Nucleotides are released in the heart under pathological conditions, but little is known about their contribution to cardiac inflammation. The present study defines the P2Y4 nucleotide receptor, expressed on cardiac microvascular endothelial cells and involved in postnatal heart development, as an important regulator of the inflammatory response to cardiac ischemia. P2Y4-null mice displayed smaller infarcts in the left descending artery ligation model, as well as reduced neutrophil infiltration and fibrosis. Gene profiling identified inter alia endothelin-1 (ET-1) as one of the target genes of P2Y4 in ischemic heart. The reduced level of ET-1 was correlated with reduction of microvascular hyperpermeability, neutrophil infiltration, and endothelial adhesion molecule expression, and it could be explained by the decreased number of endothelial cells in P2Y4-null mice. Expression analysis of metalloproteinases and their tissue inhibitors in ischemic heart revealed reduced expression of matrix metalloproteinase (MMP)-9, reported to be potentially regulated by ET-1, and MMP-8, considered as neutrophil collagenase, as well as reduction of tissue inhibitor of MMP-1 and tissue inhibitor of MMP-4 in P2Y4-null mice. Reduction of cardiac permeability and neutrophil infiltration was also observed in P2Y4-null mice in LPS-induced inflammation model. Protection against infarction resulting from loss of P2Y4 brings new therapeutic perspectives for cardiac ischemia and remodeling.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Loss of Mouse P2Y4 Nucleotide Receptor Protects against Myocardial Infarction through Endothelin-1 Downregulation

Horckmans

Esfahani

Beauloye

et al. 2015

The Journal of Immunology

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“…UTP reduced infarct size and improve heart function in rats after MI [578] and also in mice [535]. Positive inotropic effects in humans were elicited by UTP and uridine diphosphate via P2Y2R and P2Y6R, respectively [642].…”

Section: Myocardial Infarctionmentioning

confidence: 95%

“…Apyrase (CD39), which catalyses the hydrolysis of ATP to AMP, provided myocardial protection against cardiac ischaemia-reperfusion injury [534]. UTP was claimed to reduce infarct size and improve mouse heart function after myocardial infarct via P2Y2R [535].…”

Section: Ischaemiamentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

120

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This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

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Adenosine diphosphate reduces infarct size and improves porcine heart function after myocardial infarct

et al. 2013

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Acute myocardial infarction continues to be a major cause of morbidity and mortality. Timely reperfusion can substantially improve outcomes and the administration of cardioprotective substances during reperfusion is therefore highly attractive. Adenosine diphosphate (ADP) and uridine-5-triphoshate (UTP) are both released during myocardial ischemia, influencing hemodynamics. Both mediate the release of tissue plasminogen activator (t-PA), which can reduce infarct size (IS). The objective of this study was to investigate whether exogenous ADP and UTP administration during reperfusion could reduce myocardial IS and whether this correlated to t-PA release or improvements in hemodynamic responses. Hemodynamic variables and t-PA were measured in 22 pigs before, during, and after 45 min of left anterior coronary artery occlusion. During reperfusion, the pigs were randomized to 240 min of intracoronary infusion of ADP, UTP, or control (no intervention). Ischemic area compared to the area at risk [IS/AAR] was measured. [IS/AAR] was 52 ± 11% in the control animals. ADP decreased [IS/AAR] by 19% (P < 0.05), while UTP increased [IS/AAR] by 15% (P < 0.05). Cardiac output (CO) increased from 3.4 to 3.5 L/min (P < 0.05) and mean arterial pressure (MAP) decreased from 87 to 73 mmHg in the ADP group (P < 0.05). t-PA concentration increased in the ADP and UTP group from 2.0 ng/mL to 2.5 and 2.4 ng/mL, respectively (P < 0.05) but remained unchanged in the control group. In conclusion, intracoronary ADP infusion during reperfusion reduces IS by ∼20% independently from systemic release of t-PA. ADP-induced reduction in both preload and afterload could account for the beneficial myocardial effect.

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UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor

Cited by 49 publications

References 42 publications

Loss of Mouse P2Y4 Nucleotide Receptor Protects against Myocardial Infarction through Endothelin-1 Downregulation

Loss of Mouse P2Y4 Nucleotide Receptor Protects against Myocardial Infarction through Endothelin-1 Downregulation

Cardiac purinergic signalling in health and disease

Adenosine diphosphate reduces infarct size and improves porcine heart function after myocardial infarct

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