Macrophage Apoptosis in Advanced Atherosclerosis

Tabas, Ira; Seimon, Tracie A.; Timmins, Jenelle M.; Li, Gang; Lim, Wah-Seng

doi:10.1111/j.1749-6632.2009.04957.x

Cited by 91 publications

(66 citation statements)

References 51 publications

(111 reference statements)

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“…SMC apoptosis can lead to a loss of interstitial collagen fibers, resulting in unstable plaques that are prone to rupture [36,70,[72][73][74]. Taken together, these findings suggest that, since oxidative stress is closely associated with apoptosis, PRDX4 may play a key role in ameliorating atherosclerotic progression in HcD-fed apoE …”

Section: Prdx4 Protects Against Shds-induced Type 1 Dm By Suppressingsupporting

confidence: 55%

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

Yamada¹,

Guo²,

Tanimoto³

2017

Preprint

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The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. Recently, we generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

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Section: Prdx4 Protects Against Shds-induced Type 1 Dm By Suppressingsupporting

confidence: 55%

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

Yamada¹,

Guo²,

Tanimoto³

2017

Preprint

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“…Increased macrophage apoptosis promotes necrotic core expansion 44 because efferocytosis is impaired and overwhelmed, leading to secondary necrosis and inflammation. 45,46 polG −/− /ApoE −/− monocytes also had increased secretion of tumor necrosis factor-α and interleukin-1β. The proinflammatory phenotype may result from increased mitochondrial permeability transition pore opening, which leads to mtDNA release into the cytosol.…”

Section: Human Plaques Show Increased Mtdna Damage and Mtdna Damage mentioning

confidence: 98%

Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans

et al. 2013

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Background— Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species. Methods and Results— mtDNA damage occurred early in the vessel wall in apolipoprotein E–null (ApoE −/− ) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE −/− mice deficient for mitochondrial polymerase-γ proofreading activity (polG −/− /ApoE −/− ). polG −/− /ApoE −/− mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG −/− /ApoE −/− mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG −/− /ApoE −/− bone marrow increased the features of plaque vulnerability, and polG −/− /ApoE −/− monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. Conclusions— We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.

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“…TLR-mediated ER stress and apoptosis have been observed in atherosclerosis (46,53). However, mechanisms linking ER stress and inflammation are not well understood.…”

Section: Link Between Insulin Resistance and Impairment Of Vascular Amentioning

confidence: 99%

Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

Jang

Kim

Hwang

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Jang H, Kim H, Hwang DH, Quon MJ, Kim J. Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin. Am J Physiol Endocrinol Metab 304: E1077-E1088, 2013. First published March 26, 2013; doi:10.1152/ajpendo.00578.2012Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNF␣. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity. endothelial function; vascular insulin resistance; Toll-like receptor 2; unfolding protein response; inflammation; endothelial nitric oxide synthase INSULIN SIGNALING PATHWAYS involving insulin receptor/insulin receptor substrates (IRS)/phosphatidylinositol (PI) 3-kinase/ protein kinase B (Akt) contribute to glucose uptake in skeletal muscle and adipose tissue. A similar insulin signaling pathway in vascular endothelium leads to activation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO), which contribute to vasodilation and capillary recruitment (18). Vasodilator actions of insulin play important roles in antiatherogenesis and capillary recruitment that regulate hemodynamics as well as nutrient metabolism (23, 51). Impairment of vascular actions of insulin leads to a reduction of eNOS activity and endothelial dysfunction that contributes to both metabolic dysfunction and cardiovascular complications. This is evident from the metabolic and cardiovascular phenotype of eNOS knockout mice (9,18,43). High-fat diet (HFD) pro-

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Macrophage Apoptosis in Advanced Atherosclerosis

Cited by 91 publications

References 51 publications

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans

Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

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