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

Komalavilas, Padmini; Luo, Weifeng; Guth, Christy M.; Jolayemi, Olukemi; Bartelson, Rachel I.; Cheung‐Flynn, Joyce; Brophy, Colleen M.

doi:10.1371/journal.pone.0188069

Cited by 11 publications

(14 citation statements)

References 58 publications

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“… 49 P2X7-induced renal vasoconstriction causes tissue hypoxia, where along with inflammatory cytokines and reactive oxygen species, it causes inflammation, fibrosis, and glomerular dysfunction. 49 , 58 – 62 Together, renal fibrosis, increased sodium retention, and renal vasoconstriction promote a rise in blood pressure (BP) that can increase systemic circulating ATP concentrations. The resulting P2X7 activation promotes endothelial cell apoptosis, 67 , 68 vascular remodeling, and ultimately endothelial dysfunction, 62 , 71 which further exacerbates the increase in BP.…”

Section: Discussionmentioning

confidence: 99%

“… 49 Prolonged exposure to elevated extracellular ATP results in P2X7-mediated mesangial, fibroblast, endothelial, and renal tubular cell death, contributing to renal inflammation and fibrosis, as well as promoting endothelial dysfunction. 58 – 62 P2X7 antagonism results in a partially NO-dependent vasodilation of the afferent, efferent, and renal arteries, increasing renal perfusion and reducing renal inflammation and fibrosis. 49 , 50 , 52 , 54 P2X7 KO (knockout) or antagonism has also proved effective in preventing renal fibrosis, renal immune cell infiltration, and lowering BP and albuminuria in Dahl salt-sensitive rats and in a deoxycorticosterone acetate–salt model of hypertension.…”

Section: P2x7 and Kidney Functionmentioning

confidence: 99%

“… 71 A model investigating vascular surgical stretch injury demonstrated that P2X7 activation diminished endothelium-dependent relaxation through decreased NO production. 62 The resulting vascular dysfunction and remodeling can contribute to increased systemic vascular resistance and the development of hypertension. 72 , 73 …”

Section: P2x7 and Systemic Vasculaturementioning

confidence: 99%

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P2X7 Receptors

Shokoples

Paradis

Schiffrin

2021

ATVB

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Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.

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Section: Discussionmentioning

confidence: 99%

Section: P2x7 and Kidney Functionmentioning

confidence: 99%

Section: P2x7 and Systemic Vasculaturementioning

confidence: 99%

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P2X7 Receptors

Shokoples

Paradis

Schiffrin

2021

ATVB

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“…P2X7R aggravates LPS-induced vascular dysfunction and increases downstream production of inflammation [ 49 , 50 ]. Besides, P2X7R activation leads to endothelial dysfunction by impairing eNOS/NO signaling pathway [ 51 , 52 ]. However, there is insufficient evidence to suggest that P2X7R is involved in diabetes-induced endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Astragaloside IV on High Glucose-Induced Endothelial Dysfunction via Inhibition of P2X7R Dependent P38 MAPK Signaling Pathway

Leng

Liu

Sun

et al. 2020

Oxidative Medicine and Cellular Longevity

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Vascular endothelial dysfunction is associated with increased mortality in patients with diabetes. Astragaloside IV (As-IV) is a bioactive saponin with therapeutic potential as an anti-inflammatory and antiendothelial dysfunction. However, the underlying mechanism for how As-IV ameliorated endothelial dysfunction is still unclear. Therefore, in this study, we examined the protective effect of As-IV against endothelial dysfunction and explored potential molecular biology mechanism. In vivo, rats were intraperitoneally injected with streptozotocin (STZ) at a dose of 65 mg/kg body weight to establish a diabetic model. In vitro studies, rat aortic endothelial cells (RAOEC) were pretreated with As-IV, SB203580 (p38 MAPK inhibitor) for 2 h prior to the addition of high glucose (33 mM glucose). Our findings indicated that As-IV improved impaired endothelium-dependent relaxation and increased the levels of endothelial NO synthase (eNOS) and nitric oxide (NO) both in vivo and in vitro. Besides, As-IV treatment inhibited the elevated inflammation and oxidative stress in diabetic model both in vivo and in vitro. Moreover, As-IV administration reversed the upregulated expression of P2X7R and p-p38 MAPK in vivo and in vitro. Additionally, the effects of both P2X7R siRNA and SB203580 on endothelial cells were similar to As-IV. Collectively, our study demonstrated that As-IV rescued endothelial dysfunction induced by high glucose via inhibition of P2X7R dependent p38 MAPK signaling pathway. This provides a theoretical basis for the further study of the vascular endothelial protective effects of As-IV.

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“…Previous findings in our laboratory suggested that treatment of HSVEC with ATP, released after NS injury, reduces NO production [21]. NO production is regulated by synthesis (via activated eNOS) or substrate availability (via arginase).…”

Section: Resultsmentioning

confidence: 99%

Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways

et al. 2019

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Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 1β (IL-1β) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1β led to impaired endothelial relaxation. IL-1β treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.

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

Cited by 11 publications

References 58 publications

P2X7 Receptors

P2X7 Receptors

Protective Effect of Astragaloside IV on High Glucose-Induced Endothelial Dysfunction via Inhibition of P2X7R Dependent P38 MAPK Signaling Pathway

Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways

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