Inhibition of Nicotinamide Phosphoribosyltransferase Reduces Neutrophil-Mediated Injury in Myocardial Infarction

Montecucco, Fabrizio; Bauer, Inga; Braunersreuther, Vincent; Bruzzone, Santina; Akhmedov, Alexander; Lüscher, Thomas F.; Speer, Thimoteus; Poggi, Alessandro; Mannino, Elena; Pelli, Graziano; Galan, Katia; Bertolotto, Maria; Lenglet, Sébastien; Garuti, Anna; Montessuit, Christophe; Lerch, René; Pellieux, Corinne; Vuilleumier, Nicolas; Dallegri, Franco; Mage, Jacqueline; Sebastián, Carlos; Mostoslavsky, Raúl; Gayet-Ageron, Angèle; Patrone, Franco; Mach, François; Nencioni, Alessio

doi:10.1089/ars.2011.4487

Cited by 84 publications

(85 citation statements)

References 36 publications

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“…21 Thus, beside that fact Evasin-3 treatment did not improve the cerebral levels of specific inflammatory mediators of cerebral injury (such as proteases, TNF, IL-6, and other oxidants), 24,34 the selective reduction in neutrophilic ROS in the presence of Evasin-3 treatment might even be deleterious for the ischemic brain. 20,33 Our results are in partial contrast with previous studies indicating that the abrogation of poststroke neutrophil cerebral infiltration might be a promising therapeutic target to reduce brain injury during reperfusion. 21,35 However, although the majority of the article focused on neutrophil infiltration, less is known on the selective release and expression of neutrophilic products that might increase the cerebral ischemic injury.…”

Section: Evasin-3 Treatment In Ischemic Strokecontrasting

confidence: 99%

“…In fact, potent neutrophilic mediators might be differently activated by heart or brain ischemia, suggesting that the reduction in the number of infiltrated neutrophils might not be necessarily related to the degree of their activation. In addition, neutrophils might also indirectly increase (via ROS release) 20 the production of some neuroprotective mediators, such as dibrotyrosine. 21 This endogenous halogenated derivative the aromatic amino acid L-Phenylalanine has been recently shown to protect neurons from ischemic brain injury in rats.…”

Section: Evasin-3 Treatment In Ischemic Strokementioning

confidence: 99%

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Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

Copin

Silva

Fraga‐Silva

et al. 2012

J Cereb Blood Flow Metab

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Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a 'cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes.

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Section: Evasin-3 Treatment In Ischemic Strokecontrasting

confidence: 99%

Section: Evasin-3 Treatment In Ischemic Strokementioning

confidence: 99%

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

Copin

Silva

Fraga‐Silva

et al. 2012

J Cereb Blood Flow Metab

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“…Previous studies showed that intracellular nicotinamide adenine dinucleotide (NAD ϩ IL2, and IL8 (11)(12)(13)(14)(15). In line with these findings, the NAD ϩ -lowering agent FK866 (a nicotinamide phosphoribosyltransferase inhibitor) was shown to have anti-inflammatory activity in mouse models of experimental autoimmune encephalomyelitis, arthritis, polymicrobial sepsis, and heart ischemia (11)(12)(13)15).…”

Section: Cytokine Secretion By Cancer Cells Contributes To Cancer-indmentioning

confidence: 66%

The NAD+-dependent Histone Deacetylase SIRT6 Promotes Cytokine Production and Migration in Pancreatic Cancer Cells by Regulating Ca2+ Responses

Bauer

Grozio

Lasigliè

et al. 2012

Journal of Biological Chemistry

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155

128

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Background:Cytokine secretion has unwanted consequences in malignant and in inflammatory disorders. The deacetylase SIRT6 has pro-inflammatory activity, but the underlying mechanisms and its biological significance remain unclear. The relationship between inflammation and carcinogenesis has been known for many years (1). Chronic inflammation is a risk factor for cancer development. In addition, even in those cancers that do not develop in inflamed tissues, an inflammatory component is usually observed, and it is now known to be an essential part of the malignant microenvironment (2, 3). Inflammation contributes to tumorigenesis and cancer progression by supplying growth factors that sustain cancer cell proliferation and/or survival, proangiogenic factors, extracellular matrix-modifying enzymes that promote invasion and metastasis, and signals that lead to epithelial-mesenchymal transition (2, 4, 5). Moreover, increased circulating levels of pro-inflammatory cytokines are responsible for systemic manifestations of disease, such as cachexia, fever, and sweats (6 -9). Among other forms of cancer, pancreatic ductal adenocarcinoma (PDAC) 2 is well known for its propensity to secrete high levels of pro-inflammatory factors that contribute to its clinical aggressiveness and to its metastatic potential (10). The mechanisms controlling cyto-/chemokine production by inflammatory and cancer cells are only partially understood. A more detailed understanding of the molecular pathways leading to cancer-associated inflammation may lead to new therapeutic strategies with a strong impact on patient quality of life.Previous studies showed that intracellular nicotinamide adenine dinucleotide (NAD ϩ ) levels influence the capacity of inflammatory cells to secrete cytokines, such as tumor necrosis factor ␣ (TNF), interleukin 6 (IL6), IL1␤, interferon ␥ (IFN-␥), * This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Code 6108) (to A. N.), by the European Seventh Framework Program (Project 256986, PANACREAS) (to A. N.), by Ministero della Salute Grant GR-2008-1135635 (to A. N.)

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“…In line with this, a recent study reported that Sirt6 acts as a negative regulator of cardiac hypertrophy by repressing IGF/Akt signaling (90). However, in contrast with these results, inhibition of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD synthesis, reduces myocardial infarction by inhibiting neutrophil infiltration and ROS production within the infarcted hearts (91). Interestingly, the same protective phenotype was observed when Sirt6 expression was silenced, implying that although SIRT6 may protect against cardiac hypertrophy, lower SIRT6 levels may be beneficial in the context of myocardial infarction.…”

Section: Cardiovascular Diseasementioning

confidence: 85%

From Sirtuin Biology to Human Diseases: An Update

Sebastián

Satterstrom

Haigis

et al. 2012

Journal of Biological Chemistry

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210

159

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Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD ؉ -dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.Over three-quarters of a century ago, Clive McCay and colleagues first noted that rats kept on a calorie-restricted diet lived longer than freely fed controls (1). Despite the length of time that has elapsed since this discovery, the molecular mechanism that drives this life span extension has remained elusive. Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (2). Moreover, Sir2 was required for the life span of yeast to be extended by calorie restriction (3). These discoveries launched a new field in biology: the study of Sir2 and its homologs in mammals, called sirtuins.Mammals have seven sirtuins (SIRT1-7) that possess NAD ϩ -dependent deacetylase, deacylase, and ADP-ribosyltransferase activities (4). Sirtuins are found in different subcellular locations, including the nucleus (SIRT1, SIRT6, and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3-5), although in some studies, SIRT1 has been found to possess cytosolic activities, and SIRT2 has been found to associate with nuclear proteins. Sirtuins have important functions in a diverse yet interrelated set of physiological processes. In this minireview, we discuss research done in the past four years featuring their roles in aging, metabolism, cancer biology, cardiovascular disease, inflammation, and brain pathology. AgingFollowing the first publication describing a role for yeast Sir2 in promoting longevity (2), many laboratories focused on elucidating whether sirtuins might play similar roles in other organisms. Sirtuins have been shown to regulate life span in lower organisms, including yeast, nematodes, and fruit flies (5), although their role in worm and fly life span has recently been debated (6, 7). Most of these studies have described a key role for SIRT1 in regulating the metabolic response to calorie restriction (CR) 5 (8), a dietary intervention that robustly extends life span across numerous species. However, wholebody overexpression of SIRT1 in mice does not affect life span (9). Nevertheless, SIRT1 does appear to promote healthy aging by protecting against several age-related pathologies (10).The strongest link between mammalian sirtuins and the antiaging effects of CR comes from SIRT3, which mediates the prevention of age-related hearing loss by CR (11). Hearing loss is a hallmark of mammalian aging and is characterized by a gradual loss of spiral...

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Inhibition of Nicotinamide Phosphoribosyltransferase Reduces Neutrophil-Mediated Injury in Myocardial Infarction

Abstract: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice.

Cited by 84 publications

References 36 publications

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

The NAD+-dependent Histone Deacetylase SIRT6 Promotes Cytokine Production and Migration in Pancreatic Cancer Cells by Regulating Ca2+ Responses

From Sirtuin Biology to Human Diseases: An Update

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