Purinergic Signaling in the Cardiovascular System

Burnstock, Geoffrey

doi:10.1161/circresaha.116.309726

Cited by 339 publications

(320 citation statements)

References 224 publications

(212 reference statements)

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“…Many adenine nucleotides including ATP and AMP are potent vasodilators, yet they serve no benefit in regulating MI/R injury 16. Furthermore, the vasodilation seen in coronary blood flow with adenosine has been previously reported to be dependent on upregulation of NADPH‐oxidase–mediated ROS formation in coronary endothelial cells 57, 58.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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BackgroundDuring myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC‐mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.Methods and ResultsAdult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC‐mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.Conclusions MSC‐mediated conversion of AMP to adenosine by CD73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI/R injury.

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Section: Discussionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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“…8,9 The divergent vasoactive property of ATP exemplifies the dual role of purinergic signaling in the cardiovascular system. 10 Importantly, evidence for a functional role of the Panx1 channel in human vasculature is lacking, and its presence and role in skeletal muscle tissue resistance vessels in general have not been established.…”

mentioning

confidence: 99%

Probenecid Inhibits α-Adrenergic Receptor–Mediated Vasoconstriction in the Human Leg Vasculature

et al. 2018

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Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.

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“…Panx are widely expressed in the vascular bed and represent an essential pathway for the release of vasoactive purines (Billaud et al, 2012; Burns et al, 2012; Lohman et al, 2012a; Begandt et al, 2017). ATP and adenosine can dilate cerebral arteries and arterioles by activating endothelial P2 (P2Y1, P2Y2, P2Y4, P2Y6 and P2X4 subtypes and A 2a/b receptors, respectively; Ralevic and Dunn, 2015; Burnstock, 2017). Remarkably, endothelium sensitivity to ATP during the sleep-wake cycle is most pronounced at the beginning of the active phase (Durgan et al, 2016).…”

Section: Pannexins In Control Of Cerebrovascular Tonementioning

confidence: 99%

“…The mammalian purinergic system possesses two mechanisms for release of intracellular ATP: a transmembrane channel-mediated release and vesicular release (Lohman and Isakson, 2014; Burnstock, 2017). It is currently established that, along with some connexins, Panx1 hemichannels are the major conduit of non-vesicular release of intracellular ATP into the extracellular medium (Suadicani et al, 2012; Beckel et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Pannexins Are Potential New Players in the Regulation of Cerebral Homeostasis during Sleep-Wake Cycle

Shestopalov

Panchin

Tarasova

et al. 2017

Front. Cell. Neurosci.

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During brain homeostasis, both neurons and astroglia release ATP that is rapidly converted to adenosine in the extracellular space. Pannexin-1 (Panx1) hemichannels represent a major conduit of non-vesicular ATP release from brain cells. Previous studies have shown that Panx1−/− mice possess severe disruption of the sleep-wake cycle. Here, we review experimental data supporting the involvement of pannexins (Panx) in the coordination of fundamental sleep-associated brain processes, such as neuronal activity and regulation of cerebrovascular tone. Panx1 hemichannels are likely implicated in the regulation of the sleep-wake cycle via an indirect effect of released ATP on adenosine receptors and through interaction with other somnogens, such as IL-1β, TNFα and prostaglandin D2. In addition to the recently established role of Panx1 in the regulation of endothelium-dependent arterial dilation, similar signaling pathways are the major cellular component of neurovascular coupling. The new discovered role of Panx in sleep regulation may have broad implications in coordinating neuronal activity and homeostatic housekeeping processes during the sleep-wake cycle.

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Purinergic Signaling in the Cardiovascular System

Cited by 339 publications

References 224 publications

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Probenecid Inhibits α-Adrenergic Receptor–Mediated Vasoconstriction in the Human Leg Vasculature

Pannexins Are Potential New Players in the Regulation of Cerebral Homeostasis during Sleep-Wake Cycle

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