Adenosine triphosphate as a molecular mediator of the vascular response to injury

Guth, Christy M.; Luo, Weifung; Jolayemi, Olukemi; Chadalavada, Kalyan S.; Komalavilas, Padmini; Cheung‐Flynn, Joyce; Brophy, Colleen M.

doi:10.1016/j.jss.2017.03.025

Cited by 8 publications

(10 citation statements)

References 24 publications

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“…ATP is normally retained within the cytoplasm and a steep ATP concentration gradient exists between the cytoplasm (10 −3 to10 -2 M) [ 27 ] and the extracellular space (10 −9 to 10 −8 M) [ 36 ]. Thus, tissue damage would lead to rapid release of high local concentrations of ATP consistent with the concentrations of eATP used in this study [ 37 , 38 ].We have demonstrated earlier that stretch injury is associated with ATP release, P2X7R activation, and decreased contractile function in RA [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…A recently developed rat aorta (RA) model of subfailure overstretch injury showed that vascular stretch injury led to impaired contractile function that also was partially restored with inhibitors of P2X7R [ 11 , 19 ]. Since subfailure overstretch injury was associated with release of ATP in rat aorta [ 20 ] and FCF, a P2X7R inhibitor restored vasomotor dysfunction after stretch injury, P2X7R activation is postulated to play a role in stretch injury of vascular tissue.…”

Section: Introductionmentioning

confidence: 99%

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Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function

et al. 2017

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A viable vascular endothelial layer prevents vasomotor dysfunction, thrombosis, inflammation, and intimal hyperplasia. Injury to the endothelium occurs during harvest and “back table” preparation of human saphenous vein prior to implantation as an arterial bypass conduit. A subfailure overstretch model of rat aorta was used to show that subfailure stretch injury of vascular tissue leads to impaired endothelial-dependent relaxation. Stretch-induced impaired relaxation was mitigated by treatment with purinergic P2X7 receptor (P2X7R) inhibitors, brilliant blue FCF (FCF) and A740003, or apyrase, an enzyme that catalyzes the hydrolysis of ATP. Alternatively, treatment of rat aorta with exogenous ATP or 2’(3’)-O-(4-Benzoyl benzoyl)-ATP (BzATP) also impaired endothelial-dependent relaxation. Treatment of human saphenous vein endothelial cells (HSVEC) with exogenous ATP led to reduced nitric oxide production which was associated with increased phosphorylation of the stress activated protein kinase, p38 MAPK. ATP- stimulated p38 MAPK phosphorylation of HSVEC was inhibited by FCF and SB203580. Moreover, ATP inhibition of nitric oxide production in HSVEC was prevented by FCF, SB203580, L-arginine supplementation and arginase inhibition. Finally, L-arginine supplementation and arginase inhibition restored endothelial dependent relaxation after stretch injury of rat aorta. These results suggest that vascular stretch injury leads to ATP release, activation of P2X7R and p38 MAPK resulting in endothelial dysfunction due to arginase activation. Endothelial function can be restored in both ATP treated HSVEC and intact stretch injured rat aorta by P2X7 receptor inhibition with FCF or L-arginine supplementation, implicating straightforward therapeutic options for treatment of surgical vascular injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function

et al. 2017

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“…As ATP is released into the bloodstream as a vascular response to stress or injury, its signalling function is particularly relevant in pathologies related to blood vessels [143]. Red blood cells (RBCs) modulate vasodilation by releasing ATP when oxygen concentrations decrease [144,145].…”

Section: Pathologies Related To Blood Vesselsmentioning

confidence: 99%

Approaches to Monitor ATP Levels in Living Cells: Where Do We Stand?

Ley-Ngardigal¹,

Bertolin²

2021

Preprint

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ATP is the most universal and essential energy molecule in the eukaryotic cell. This is due to its ability to store energy in form of high energy phosphate bonds, which are extremely stable and readily usable by the cell. This energy is key for a variety of biological functions such as cell growth and division, metabolism, signalling, and for the turnover of biomolecules. Understanding how ATP is produced and hydrolysed with a spatiotemporal resolution is necessary to understand its functions both in physiological and pathological contexts. In this review, we will first describe the ATP synthase, the main molecular motor for ATP production in mitochondria. Second, we will review the biochemical assays currently available to estimate ATP quantities in cells, and we will compare their readouts, strengths and weaknesses. Then, we will explore the palette of genetically-encoded biosensors designed for microscope-based approaches and show how their spatiotemporal resolution opened up the possibility to follow ATP levels and production in living cells. Finally, we will comment on how ATP monitoring is used in preclinical practices, and to what extent genetically-encoded sensors could be used as a promising tool to elucidate pathologies in which ATP is implicated.

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“…The P2X7 receptor (P2X7R), which primarily acts via NLRP3 inflammasome‐mediated signaling, has been shown to be critical for bacterial killing in monocytes and macrophages (Csoka et al, 2015 ; Hill et al, 2010 ), but the role of P2X7R on the endothelium during sepsis has not been well characterized. Our group previously showed that activation of P2X7R leads to impaired endothelial‐dependent relaxation in response to stretch injury (Guth et al, 2017 ; Komalavilas et al, 2017 ; Luo et al, 2016 , 2017 ), exogenous ATP stimulation (Guth et al, 2017 ; Komalavilas et al, 2017 ), and acidic normal saline solutions (Cheung‐Flynn et al, 2019 ). Additionally, other groups have identified a protective role for P2X7R antagonism in several experimental models of sepsis (Arulkumaran et al, 2018 ; Santana et al, 2015 ; Savio et al, 2017 ; Wu et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Blocking P2X7 receptor with AZ 10606120 exacerbates vascular hyperpermeability and inflammation in murine polymicrobial sepsis

Meegan

Komalavilas

Cheung‐Flynn

et al. 2022

Physiological Reports

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Sepsis is a devastating disease with high morbidity and mortality and no specific treatments. The pathophysiology of sepsis involves a hyperinflammatory response and release of damage‐associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), from activated and dying cells. Purinergic receptors activated by ATP have gained attention for their roles in sepsis, which can be pro‐ or anti‐inflammatory depending on the context. Current data regarding the role of ATP‐specific purinergic receptor P2X7 (P2X7R) in vascular function and inflammation during sepsis are conflicting, and its role on the endothelium has not been well characterized. In this study, we hypothesized that the P2X7R antagonist AZ 10606120 (AZ106) would prevent endothelial dysfunction during sepsis. As proof of concept, we first demonstrated the ability of AZ106 (10 µM) to prevent endothelial dysfunction in intact rat aorta in response to IL‐1β, an inflammatory mediator upregulated during sepsis. Likewise, blocking P2X7R with AZ106 (10 µg/g) reduced the impairment of endothelial‐dependent relaxation in mice subjected to intraperitoneal injection of cecal slurry (CS), a model of polymicrobial sepsis. However, contrary to our hypothesis, AZ106 did not improve microvascular permeability or injury, lung apoptosis, or illness severity in mice subjected to CS. Instead, AZ106 elevated spleen bacterial burden and circulating inflammatory markers. In conclusion, antagonism of P2X7R signaling during sepsis appears to disrupt the balance between its roles in inflammatory, antimicrobial, and vascular function.

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Adenosine triphosphate as a molecular mediator of the vascular response to injury

Cited by 8 publications

References 24 publications

Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function

Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function

Approaches to Monitor ATP Levels in Living Cells: Where Do We Stand?

Blocking P2X7 receptor with AZ 10606120 exacerbates vascular hyperpermeability and inflammation in murine polymicrobial sepsis

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