Myeloperoxidase Inhibition Improves Ventricular Function and Remodeling After Experimental Myocardial Infarction

Ali, Muhammad; Pulli, Benjamin; Courties, Gabriel; Tricot, Benoit; Sebas, Matthew; Iwamoto, Yoshiko; Hilgendorf, Ingo; Schob, Stefan; Dong, Anping; Zheng, Wei; Skoura, Athanasia; Kalgukar, Amit; Cortés, Christian; Ruggeri, Roger B.; Świrski, Filip K.; Nahrendorf, Matthias; Buckbinder, Leonard; Chen, John W.

doi:10.1016/j.jacbts.2016.09.004

Cited by 79 publications

(98 citation statements)

References 44 publications

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“…We provided several lines of evidence that serotonin-induced degranulation in neutrophils increased the surface expression of granule-stored CD11b 27,42 and the release of MPO known to enhance tissue damage in concert with reactive oxygen species. 13,43 First, we found that serotonin elicits CD11b, but not CD11a, surface expression in neutrophils, but not monocytes, as CD11a is not stored in intracellular granules 44 and monocytes are almost devoid of those. Second, vesicle transport inhibition blocked the increase of CD11b surface expression.…”

Section: Original Research Articlementioning

confidence: 78%

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Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

et al. 2019

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BACKGROUND: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. METHODS:Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. RESULTS:Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H 2 O 2 ) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Longterm serotonin reuptake inhibition-reported to protect patients with depression from cardiovascular events-resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. CONCLUSIONS:Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.

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Section: Original Research Articlementioning

confidence: 78%

“…Indeed, serotonin induced exocytosis of neutrophil granules, thereby increasing the surface expression of the β2-integrin CD11b, mediating cell adhesion to platelets and the endothelium, and releasing myeloperoxidase (MPO) and hydrogen peroxide (H 2 O 2 ), which altogether impaired healing after myocardial infarction. 13…”

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confidence: 99%

Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

et al. 2019

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“…To evaluate the specificity of 18 F-MAPP, we treated the CFA mice with either an MPO-specific irreversible inhibitor, PF-1355 (15,23), or with vehicle. Uptake of 18 F-MAPP in the treated group decreased significantly compared with that of the control group as the result of the MPO activity inhibited by PF-1355 after accounting for the contralateral PBS-injected paw as control, using SUV ratios (SUVR) between the 2 sides (Fig.…”

Section: Radiochemistrymentioning

confidence: 99%

“…MPO and its products not only kill pathogens in host defense but also oxidize lipids, proteins, DNA, and RNA to cause protein aggregation, cell signaling interruption, mutagenesis, and tissue damage (11). MPO and its excessive production of oxidants are implicated in a variety of acute and chronic diseases, including atherosclerosis (12), atrial fibrillation (13), myocardial infarction (14,15), Alzheimer's disease (16), multiple sclerosis (17,18), Parkinson's disease (19), and vasculitis (20). To combat MPO's deleterious effects, MPO inhibitors are being developed and tested in animal and human studies, which include PF-2999 for cardiovascular diseases (21), AZD3241 for Parkinson's disease (22), and PF-1355 for vasculitis and glomerulonephritis (23), among others.…”

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confidence: 99%

An activatable PET imaging radioprobe is a dynamic reporter of myeloperoxidase activity in vivo

Wang

Keliher

Zeller

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Myeloperoxidase (MPO) is a critical proinflammatory enzyme implicated in cardiovascular, neurological, and rheumatological diseases. Emerging therapies targeting inflammation have raised interest in tracking MPO activity in patients. We describe 18 F-MAPP, an activatable MPO activity radioprobe for positron emission tomography (PET) imaging. The activated radioprobe binds to proteins and accumulates at sites of MPO activity. The radioprobe 18 F-MAPP has a short blood half-life, remains stable in plasma, does not demonstrate cytotoxicity, and crosses the intact blood-brain barrier. The 18 F-MAPP imaging detected sites of elevated MPO activity in living mice embedded with human MPO and in mice induced with chemical inflammation or myocardial infarction. The 18 F-MAPP PET imaging noninvasively differentiated varying amounts of MPO activity, competitive inhibition, and MPO deficiency in living animals, confirming specificity and showing that the radioprobe can quantify changes in in vivo MPO activity. The radiosynthesis has been optimized and automated, an important step in translation. These data indicate that 18 F-MAPP is a promising translational candidate to noninvasively monitor MPO activity and inflammation in patients.

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“…It has been proposed for the treatment of vasculitis where it is efficacious in reducing edema, neutrophil accumulation, production of proinflammatory cytokines and inflammation [92,93]. …”

Section: Inhibition Of the Vanins–mpo Axismentioning

confidence: 99%

Role of the Vanins–Myeloperoxidase Axis in Colorectal Carcinogenesis

Mariani

Roncucci

2017

IJMS

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The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α.

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Myeloperoxidase Inhibition Improves Ventricular Function and Remodeling After Experimental Myocardial Infarction

Abstract: Visual Abstract

Cited by 79 publications

References 44 publications

Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

An activatable PET imaging radioprobe is a dynamic reporter of myeloperoxidase activity in vivo

Role of the Vanins–Myeloperoxidase Axis in Colorectal Carcinogenesis

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