Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

Mastrocola, Raffaella; Penna, Cláudia; Tullio, Francesca; Femminò, Saveria; Nigro, Debora; Chiazza, Fausto; Serpe, Loredana; Collotta, Debora; Alloatti, Giuseppe; Cocco, Mattia; Bertinaria, Massimo; Pagliaro, Pasquale; Aragno, Manuela; Collino, Massimo

doi:10.1155/2016/5271251

Cited by 115 publications

(90 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was shown to be protective against NLRP3-involved myocardial I/R in a rat model (Mastrocola et al, 2016). Further rigorous investigations are needed to evaluate the effects of INF4E on neurological diseases and its side effects.…”

Section: Targeting the Nlrp3 Inflammasome For The Treatment Of Neurolmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

353

275

View full text Add to dashboard Cite

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

show abstract

Section: Targeting the Nlrp3 Inflammasome For The Treatment Of Neurolmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

353

275

View full text Add to dashboard Cite

show abstract

“…In 2013, Sandanger et al reported a reduced infarct size in Nlrp3 −/− mice in an ex vivo Langendorff perfused heart model of IR . Also using isolated hearts, it was confirmed that pre‐treatment with the NLRP3 inhibitor, INF4E, reduced infarct size and improved ventricular developed pressure after IR . These findings were confirmed by Luo et al in a type 2 diabetes rat model …”

Section: Pyroptosismentioning

confidence: 75%

“…Despite the fact that IR‐damaged myocardium releases a combination of priming and triggering factors of the NLRP3 inflammasome, it has been proposed that the NLRP3 inflammasome in the heart is not sufficient to respond to a trigger signal in the absence of a priming . Actually, after IR, the size of the infarct is found to increase more in the presence of an active NLRP3, especially if metabolic syndrome has primed the inflammasome …”

Section: Pyroptosismentioning

confidence: 99%

Mitochondrial and mitochondrial‐independent pathways of myocardial cell death during ischaemia and reperfusion injury

Davidson

Adameová

Barile³

et al. 2020

J Cellular Molecular Medi

Self Cite

130

108

View full text Add to dashboard Cite

Acute myocardial infarction causes lethal injury to cardiomyocytes during both ischaemia and reperfusion (IR). It is important to define the precise mechanisms by which they die in order to develop strategies to protect the heart from IR injury. Necrosis is known to play a major role in myocardial IR injury. There is also evidence for significant myocardial death by other pathways such as apoptosis, although this has been challenged. Mitochondria play a central role in both of these pathways of cell death, as either a causal mechanism is the case of mitochondrial permeability transition leading to necrosis, or as part of the signalling pathway in mitochondrial cytochrome c release and apoptosis. Autophagy may impact this process by removing dysfunctional proteins or even entire mitochondria through a process called mitophagy. More recently, roles for other programmed mechanisms of cell death such as necroptosis and pyroptosis have been described, and inhibitors of these pathways have been shown to be cardioprotective. In this review, we discuss both mitochondrial and mitochondrial‐independent pathways of the major modes of cell death, their role in IR injury and their potential to be targeted as part of a cardioprotective strategy. This article is part of a special Issue entitled ‘Mitochondria as targets of acute cardioprotection’ and emerged as part of the discussions of the European Union (EU)‐CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

show abstract

“…The NLRP3 inflammasome is a large multimeric protein complex mediating the cleavage of inactive 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 prointerleukin-(IL-) 1 and IL-18 into their active form [94]. We have recently provided evidence that activation of NLRP3 inflammasome contributes to the development of insulin resistance and dietinduced renal and myocardial dysfunctions, mainly by inducing IL-1 and IL-18 overproduction [95][96][97]. Activation of the endothelial NLPR3 inflammasome by injurious adipokines such as visfatin may disrupt inter-endothelial junctions and increase paracellular permeability of the endothelium contributing to the early onset of endothelial injury during metabolic disorders [98].…”

Section: Endothelial Dysfunction and Metaflammationmentioning

confidence: 99%

“…At present, efficacious NLRP3 inflammasome inhibitors are still under development. We recently contributed to characterize the cardiovascular effect of the small molecule INF4E, one of the few compounds that has been demonstrated to directly target the NLRP3 inflammasome and inhibit the ATPase activity of NLRP3 required for its activation [97]. Similar cardiovascular protective effects have been recently documented by using another small molecule which prevents the formation of the NLRP3 inflammasome complex in cardiomiocytes, thus ameliorating cardiac function after ischemia/reperfusion injury [188].…”

Section: Nlrp3 Inflammasome Inhibitors -mentioning

confidence: 99%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

Nacci

Salvia

et al. 2017

Pharmacological Research

Self Cite

View full text Add to dashboard Cite

Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

show abstract

Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

Cited by 115 publications

References 42 publications

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Mitochondrial and mitochondrial‐independent pathways of myocardial cell death during ischaemia and reperfusion injury

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Contact Info

Product

Resources

About