The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease

Shirai, Toshikazu; Nazarewicz, Ryszard; Wallis, Barbara B.; Yanes, Rolando E.; Watanabe, Ryu; Hilhorst, Marc; Tian, Lu; Harrison, David G.; Giacomini, John C.; Assimes, Themistocles L.; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1084/jem.20150900

Cited by 397 publications

(372 citation statements)

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“…95 Recent studies indicate an important role of macrophage mitochondrial oxidative stress in atherosclerosis. [96][97][98] Wang et al 96 used a mitochondrial catalase transgenic mouse, which can quench mitochondrial ROS and protect against mitochondrial ROS-induced damage in vivo. Both mouse models, including transplantation of mitochondrial catalase transgenic bone marrow cells into Ldlr −/− mice and macrophage-specific mitochondrial catalase transgenic mice in Ldlr −/− background, showed decreased inflammatory monocyte infiltration, mitochondrial ROS in lesional macrophages, and attenuation of atherosclerosis lesions.…”

Section: Nowak Et Al Oxidative Stress and Atherosclerosis E47mentioning

confidence: 99%

“…Another recent study in human monocyte/macrophage provides further evidence of mitochondrial ROS regulation in human macrophages. 97 Shirai et al 97 isolated monocytes from patients with atherosclerotic coronary artery disease and showed that monocyte-derived macrophages from the patients produced more IL-6 and IL-1β, which was highly dependent on mitochondrial ROS but not Nox2. Neither Nox2 siRNA knockdown by nor Nox2 inhibition by gp91dstat had any effects on cytokine production.…”

Section: Nowak Et Al Oxidative Stress and Atherosclerosis E47mentioning

confidence: 99%

“…However, mitoTEMPO, a mitochondria-target ROS scavenger, significantly reduced IL-6 and IL-1β production in macrophages from the patients, indicating a critical role of ROS from mitochondria, but not Nox2, in regulating cytokine production in macrophages derived from atherosclerotic patients. 97 Besides, Tumurkhuu et al 98 demonstrated 8-oxoguanine glycosylase, a major DNA glycosylase responsible for removing mitochondrial oxidative stress-induced DNA damage, plays a protective role in atherosclerosis by preventing excessive inflammasome activation in macrophages, further supporting the critical role of macrophage mitochondrial oxidative stress in promoting atherosclerosis.…”

Section: Nowak Et Al Oxidative Stress and Atherosclerosis E47mentioning

confidence: 99%

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Reactive Oxygen Species Generation and Atherosclerosis

Nowak

Deng

Ruan

et al. 2017

ATVB

115

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Section: Nowak Et Al Oxidative Stress and Atherosclerosis E47mentioning

confidence: 99%

Section: Nowak Et Al Oxidative Stress and Atherosclerosis E47mentioning

confidence: 99%

Section: Nowak Et Al Oxidative Stress and Atherosclerosis E47mentioning

confidence: 99%

See 1 more Smart Citation

Reactive Oxygen Species Generation and Atherosclerosis

Nowak

Deng

Ruan

et al. 2017

ATVB

115

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“…Classically- and alternatively-activated MΦs are detected in atherosclerotic lesions [30]. The classical M1-like MΦ has been reported to be associated with plaque progression, while the immunosuppressive alternatively-activated M2-like phenotype is associated with smaller lesions and regression of plaques [13, 16, 31–36]. We previously reported that pro-inflammatory activation is achievable by enhancing glucose metabolism via glucose transporter 1 (GLUT1) overexpression using an in vitro model - even in the absence of external stimuli [37] - in a demonstration of the tight immunometabolic link between MΦ metabolic reprogramming and activation state.…”

Section: Discussionmentioning

confidence: 99%

“…MΦ-mediated inflammation is a critical component of atherosclerotic plaque formation with MΦ glycolysis associated with poorer outcomes [16]. Atherosclerosis is an ongoing inflammatory process, during which MΦs mediate all stages of the disease, from initiation through progression and, ultimately, thrombotic complications, as well as resolution [1].…”

Section: Introductionmentioning

confidence: 99%

Lack of myeloid Fatp1 increases atherosclerotic lesion size in Ldlr −/− mice

et al. 2017

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Background and aims Altered metabolism is an important regulator of macrophage (MΦ) phenotype, which contributes to inflammatory diseases such as atherosclerosis. Broadly, pro-inflammatory, classically-activated MΦs (CAM) are glycolytic while alternatively-activated MΦs (AAM) oxidize fatty acids, although overlap exists. We previously demonstrated that MΦ fatty acid transport protein 1 (FATP1, Slc27a1) was necessary to maintain the oxidative and anti-inflammatory AAM phenotype in vivo in a model of diet-induced obesity. The aim of this study was to examine how MΦ metabolic reprogramming through FATP1 ablation affects the process of atherogenesis. We hypothesized that FATP1 limits MΦ-mediated inflammation during atherogenesis. Thus, mice lacking MΦ Fatp1 would display elevated formation of atherosclerotic lesions in a mouse model lacking the low-density lipoprotein (LDL) receptor (Ldlr−/−). Methods We transplanted bone marrow collected from Fatp1+/+ or Fatp1−/− mice into Ldlr−/− mice and fed chimeric mice a Western diet for 12 weeks. Body weight, blood glucose, and plasma lipids were measured. Aortic sinus and aorta lesions were quantified. Atherosclerotic plaque composition, oxidative stress, and inflammation were analyzed histologically. Results Compared to Fatp1+/+Ldlr−/− mice, Fatp1−/−Ldlr−/− mice exhibited significantly larger lesion area and elevated oxidative stress and inflammation in the atherosclerotic plaque. Macrophage and smooth muscle cell content did not differ by Fatp1 genotype. There were no significant systemic alterations in LDL, high-density lipoprotein (HDL), total cholesterol, or triacylglyceride, suggesting that the effect was local to the cells of the vessel microenvironment in a Fatp1-dependent manner. Conclusions MΦ Fatp1 limits atherogenesis and may be a viable target to metabolically reprogram MΦs.

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Macrophage metabolism in atherosclerosis

2017

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A key aspect of atherosclerosis is the maladaptive inflammatory response to lipoprotein accumulation in the artery. The failure to decrease lipid accumulation, to clear apoptotic cells, and to resolve inflammation ultimately leads to macrophage accumulation within the vascular wall [Thorp EB (2010) Apoptosis 15, 1124–1136; Moore K et al. (2013) Nat Rev Immunol 13, 709–721; Moore KJ and Tabas I (2011) Cell 145, 341–355; Ley K et al. (2011) Arterioscler Thromb Vasc Biol 31, 1506–1516]. Several subsets of macrophages are found inside atherosclerotic plaques [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17; Leitinger N and Schulman IG (2013) Arterioscler Thromb Vasc Biol 33, 1120–1126; Mantovani A et al. (2009) Arterioscler Thromb Vasc Biol 29, 1419–1423]: Proinflammatory M1‐like macrophages potentially participate in atherosclerosis initiation and progression; M2‐like macrophages are thought to be protective due to their anti‐inflammatory and profibrotic properties, presumably stabilizing the plaque [Chistiakov DA et al. (2015) Int J Cardiol 184, 436–445; Gordon S (2003) Nat Rev Immunol 3, 23–35]; Mox macrophages develop in response to oxidized phospholipids and present a glutathione‐ and potentially redox‐regulating phenotype [Kadl A et al. (2010) Circ Res 107, 737–746]; Mhem macrophages are found in areas of plaque hemorrhage [Boyle JJ et al. (2009) Am J Pathol 174, 1097–1108; Boyle JJ et al. (2012) Circ Res 110, 20–33] where they are involved in heme clearance. Recent evidence suggests that the relative abundance of these macrophage subsets is a better indicator of plaque progression and stability than the total number of lesion macrophages [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17]. Over the last few years, findings in the area of immunometabolism established a link between the metabolic state of the different macrophage phenotypes and their functions [O'Neill LAJ and Pearce EJ (2016) J Exp Med 213, 15–23]. However, the effect of metabolic changes in macrophages on atherosclerotic plaque progression and stability is not well understood and an area of intensive study. In this review, we will summarize and critically discuss recent developments in the field of macrophage metabolism in the context of atherosclerosis to guide future investigation in this area.

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The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease

Abstract: Shirai et al. show that the glycolytic enzyme PKM2 serves as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation in macrophages from patients with atherosclerotic coronary artery disease.

Cited by 397 publications

References 71 publications

Reactive Oxygen Species Generation and Atherosclerosis

Reactive Oxygen Species Generation and Atherosclerosis

Lack of myeloid Fatp1 increases atherosclerotic lesion size in Ldlr −/− mice

Macrophage metabolism in atherosclerosis

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