Endothelial Pannexin 1 Regulates Cardiac Response to Myocardial Infarction

Good, Miranda E.; Young, A. P.; Wolpe, Abigail G.; Ma, Mingxing; Hall, P.; Duffy, Colleen; Aronovitz, Mark; Martin, Gregory L.; Blanton, Robert M.; Leitinger, Norbert; Johnstone, Scott R.; Wolf, Matthew J.; Isakson, Brant E.

doi:10.1161/circresaha.120.317272

Cited by 16 publications

(28 citation statements)

References 5 publications

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“…54,55 A recent study has also confirmed that probenecid improves cardiac function at early phase of post-infarction HF via inhibiting endothelial PANX1 channels and consequential leukocyte infiltration. 56 Therefore, we propose that probenecid might be a 'broad-spectrum' inflammasome inhibitor besides its well-characterized uricosuric properties. Probenecid has been previously demonstrated to improve outcome in an animal model of ischaemic HF with a shorter 4-week follow-up period by exerting positive inotropic effects via transient receptor potential vanilloid type-2 (TRPV2), and the positive inotropic effect was confirmed in a small number of patients with HFrEF.…”

Section: Discussionmentioning

confidence: 98%

AIM2-driven inflammasome activation in heart failure

Onódi

Ruppert

Kucsera

et al. 2021

Cardiovascular Research

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Aims Interleukin-1β (IL-1β) is an important pathogenic factor in cardiovascular diseases including chronic heart failure (HF). The CANTOS trial highlighted that inflammasomes as primary sources of IL-1 β are promising new therapeutic targets in cardiovascular diseases. Therefore, we aimed to assess inflammasome activation in failing hearts to identify activation patterns of inflammasome subtypes as sources of IL-1β. Methods and Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human heart failure regardless of the etiology (ischemic or dilated cardiomyopathy) while the NLRP1/NALP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change in HF samples. AIM2 expression was primarily detected in monocytes/macrophages of failing hearts. Translational animal models of HF (pressure or volume overload, and permanent coronary artery ligation in rat, as well as ischemia/reperfusion-induced HF in pigs) demonstrated activation pattern of AIM2 similar to that of observed in end-stages of human HF. In vitro AIM2 inflammasome activation in human THP-1 monocytic cells and human AC16 cells was significantly reduced by pharmacological blockade of pannexin-1 channels by the clinically used uricosuric drug probenecid. Probenecid was also able to reduce pressure overload-induced mortality and restore indices of disease severity in a rat chronic HF model in vivo. Conclusions This is the first report showing that AIM2 and NLRC4 inflammasome activation contribute to chronic inflammation in heart failure and that probenecid alleviates chronic HF by reducing inflammasome activation. The present translational study suggests the possibility of repositioning of probenecid for HF indications.

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Section: Discussionmentioning

confidence: 98%

AIM2-driven inflammasome activation in heart failure

Onódi

Ruppert

Kucsera

et al. 2021

Cardiovascular Research

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“…Previous studies have found that P2Y2 receptor-mediated vasoconstriction is reduced in coronary arteries following IRI, possibly due to a compensatory mechanism to combat the increased extracellular ATP during IRI [ 103 ]. Deletion of endothelial Panx1 or pharmacological inhibition of Panx1 at time of reperfusion protected cardiac function following IRI, although without a change in infarct volume [ 13 ]. This is hypothesized to be due to a reduction in pro-inflammatory macrophage infiltration into the non-injured cardiac tissue [ 13 ].…”

Section: Heartmentioning

confidence: 99%

“…Deletion of endothelial Panx1 or pharmacological inhibition of Panx1 at time of reperfusion protected cardiac function following IRI, although without a change in infarct volume [ 13 ]. This is hypothesized to be due to a reduction in pro-inflammatory macrophage infiltration into the non-injured cardiac tissue [ 13 ]. Together, these data suggest an important role for Panx1 in myocardial infarction; however, further studies are needed to understand the cell type-specific roles and potential beneficial versus detrimental roles of Panx1 in determining post-IRI cardiac function and outcome.…”

Section: Heartmentioning

confidence: 99%

“…Pannexin channels have been linked to pathophysiological processes related to the vasculature, including hypertension [5][6][7][8], stroke [9,10], and inflammation/ischemic injury [11][12][13][14][15], possibly including complications due to COVID-19 [16]. In this review, we summarize current progress in identifying roles for the most ubiquitous pannexin isoform, Panx1, in regulating how the vasculature reacts to injury and inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Pannexin 1 as a driver of inflammation and ischemia–reperfusion injury

Koval

Cwiek

Carr

et al. 2021

Purinergic Signalling

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Pannexin 1 (Panx1) is a ubiquitously expressed protein forming large conductance channels that are central to many distinct inflammation and injury responses. There is accumulating evidence showing ATP released from Panx1 channels, as well as metabolites, provide effective paracrine and autocrine signaling molecules that regulate different elements of the injury response. As channels with a broad range of permselectivity, Panx1 channels mediate the secretion and uptake of multiple solutes, ranging from calcium to bacterial derived molecules. In this review, we describe how Panx1 functions in response to different pro-inflammatory stimuli, focusing mainly on signaling coordinated by the vasculature. How Panx1 mediates ATP release by injured cells is also discussed. The ability of Panx1 to serve as a central component of many diverse physiologic responses has proven to be critically dependent on the context of expression, post-translational modification, interacting partners, and the mode of stimulation.

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“…Several drugs exhibit utility in blocking PANX1 function, but in almost all cases these pharmacological agents have multiple molecular targets. Probenecid was used to treat gout, but it is possibly the best-known PANX1 blocker in vitro and in vivo that continues to be deployed in many preclinical models, the latest of which includes myocardial infracts [63]. Together with a drug historically used in ulcer treatment (carbenoxolone), probenecid may have efficacy in treating tumors with high PANX1 levels.…”

Section: Clinically Deployed Drugs Targeting Pannexins That May Have Utility In Cancer Treatmentsmentioning

confidence: 99%