Subfailure Overstretch Injury Leads to Reversible Functional Impairment and Purinergic P2X7 Receptor Activation in Intact Vascular Tissue

Luo, Weifeng; Guth, Christy M.; Jolayemi, Olukemi; Duvall, Craig L.; Brophy, Colleen M.; Cheung‐Flynn, Joyce

doi:10.3389/fbioe.2016.00075

Cited by 7 publications

(26 citation statements)

References 41 publications

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“…P2X7R antagonism restores stretch-induced loss of contractile functions and prevents eATP release in RA We previously showed that P2X7R is activated by subfailure overstretch in the RA model [15]. Immunohistochemical staining of RA showed that P2X7R is expressed in the medial and endothelial layers of RA (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Subfailure overstretch injury impairs functional responses and causes release of extracellular ATP in RA To examine mechanical injury to vein graft under controlled conditions, we previously developed a subfailure overstretch (longitudinal) injury model using isolated rat abdominal aorta (RA) [15]. Subfailure overstretch injury impaired the contractile response of isolated RA to depolarizing KCl (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To determine the molecular mechanisms by which injury leads to decreased function and viability of HSV, a model of traction injury using RA was developed where the haptic endpoint of stretch during vein harvest is simulated [15]. While studies using cultured vascular cells to modeled mechanical stretch offer insight into molecular signaling that determine cell fate (reviewed in [42,43]), very few studied the effects of pathologic stretch in intact tissues [40,44,45].…”

Section: Discussionmentioning

confidence: 99%

“…This stretch injury recapitulates the haptic endpoint of traction during endoscopic harvest of HSV. Subfailure overstretch injury to RA leads to impaired physiologic function that can be partially restored with A438079 and oxidized ATP, inhibitors to the purinergic P2X7 receptor (P2X7R), further implicating a role of P2X7R signaling in iatrogenic stretch injury to the conduits [15].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently developed a rat aorta (RA) model of subfailure overstretch injury [15]. This stretch injury recapitulates the haptic endpoint of traction during endoscopic harvest of HSV.…”

Section: Introductionmentioning

confidence: 99%

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P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

Luo

Feldman

McCallister

et al. 2017

Purinergic Signalling

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Human saphenous vein (HSV) is harvested and prepared prior to implantation as an arterial bypass graft. Injury and the response to injury from surgical harvest and preparation trigger cascades of molecular events and contribute to graft remodeling and intimal hyperplasia. Apoptosis is an early response after implantation that contributes the development of neointimal lesions. Here, we showed that surgical harvest and preparation of HSV leads to vasomotor dysfunction, increased apoptosis and downregulation of the phosphorylation of the anti-apoptotic protein, Niban. A model of subfailure overstretch injury in rat aorta (RA) was used to demonstrate impaired vasomotor function, increased extracellular ATP (eATP) release, and increased apoptosis following pathological vascular injury. The subfailure overstretch injury was associated with activation of p38 MAPK stress pathway and decreases in the phosphorylation of the anti-apoptotic protein Niban. Treatment of RA after overstretch injury with antagonists to purinergic P2X7 receptor (P2X7R) antagonists or P2X7R/pannexin (PanX1) complex, but not PanX1 alone, restored vasomotor function. Inhibitors to P2X7R and PanX1 reduced stretch-induced eATP release. P2X7R/PanX1 antagonism led to decrease in p38 MAPK phosphorylation, restoration of Niban phosphorylation and increases in the phosphorylation of the anti-apoptotic protein Akt in RA and reduced TNFα-stimulated caspase 3/7 activity in cultured rat vascular smooth muscle cells. In conclusion, inhibition of P2X7R after overstretch injury restored vasomotor function and inhibited apoptosis. Treatment with P2X7R/PanX1 complex inhibitors after harvest and preparation injury of blood vessels used for bypass conduits may prevent the subsequent response to injury that lead to apoptosis and represents a novel therapeutic approach to prevent graft failure.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

Luo

Feldman

McCallister

et al. 2017

Purinergic Signalling

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The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Burnstock

Knight

2017

Purinergic Signalling

195

166

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Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.

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

Guth

Luo

Jolayemi

et al. 2017

Journal of Surgical Research

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Background Human saphenous veins used for arterial bypass undergo stretch injury at the time of harvest and pre-implant preparation. Vascular injury promotes intimal hyperplasia, the leading cause of graft failure, but the molecular events leading to this response are largely unknown. This study investigated adenosine triphosphate (ATP) as a potential molecular mediator in the vascular response to stretch injury, and the downstream effects of the purinergic receptor, P2X7R, and p38 MAPK activation. Materials and Methods A subfailure stretch rat aorta model was employed to determine the effect of stretch injury on release of ATP and vasomotor responses. Stretch-injured tissues were treated with apyrase, the P2X7R antagonist, A438079, or the p38 MAPK inhibitor, SB203580, and subsequent contractile forces were measured using a muscle bath. An exogenous ATP (eATP) injury model was developed and the experiment repeated. Change in p38 MAPK phosphorylation after stretch and eATP tissue injury was determined using Western blotting. Non-injured tissue was incubated in the p38 MAPK activator, anisomycin, and subsequent contractile function and p38 MAPK phosphorylation were analyzed. Results Stretch injury was associated with release of ATP. Contractile function was decreased in tissue subjected to subfailure stretch, eATP, and anisomycin. Contractile function was restored by apyrase, P2X7R antagonism, and p38-MAPK inhibition. Stretch, eATP, and anisomycin-injured tissue demonstrated increased phosphorylation of p38 MAPK. Conclusions Taken together these data suggest that the vascular response to stretch injury is associated with release of ATP and activation of the P2X7R/P38 MAPK pathway, resulting in contractile dysfunction. Modulation of this pathway in vein grafts after harvest and before implantation may reduce the vascular response to injury.

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Subfailure Overstretch Injury Leads to Reversible Functional Impairment and Purinergic P2X7 Receptor Activation in Intact Vascular Tissue

Cited by 7 publications

References 41 publications

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

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

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