Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis

Ullevig, Sarah L.; Zhao, Qiu; Zamora, Debora A.; Asmis, Reto

doi:10.1016/j.atherosclerosis.2011.06.013

Cited by 77 publications

(72 citation statements)

References 41 publications

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“…There are two previous studies that investigated the effects of UA on atherosclerosis using mouse models that obtained opposite results. Ullevig et al (31) showed that UA enhances autophagy in macrophages by increasing expression of autophagy-related proteins Atg5 and Atg16l1. Autophagosome sequesters pro-IL-1 and leads to pro-IL-1 degradation in lysosomes, diverting it from being processed by caspase 1 into mature IL-1 for secretion.…”

Section: Discussionmentioning

confidence: 99%

“…These beneficial properties are of apparent value for the treatment of atherosclerosis, although the underlying molecular mechanisms are largely unknown. Indeed, limited animal studies have shown the potential anti-atherogenic effects of UA (31). Our recent finding that UA promotes cancer cell autophagy (32) prompted us to determine whether this autophagy-enhancing function also holds true in macrophages.…”

Section: Mtt Assaymentioning

confidence: 99%

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Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Leng

Iwanowycz

Saaoud

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org recycled for downstream metabolism (1). Among the three major kinds of autophagy, macroautophagy, microautophagy, and chaperone-mediated autophagy, macroautophagy is the most prevalent form and, thus, commonly referred to as autophagy (2, 3). Over the past decade, research efforts regarding this ancient biological process have been revived due to the realization that alterations in autophagy play crucial pathological roles in many diseases (4, 5) for which current therapeutic means are limited. While many basic aspects of autophagy have been unraveled, little has been translated into clinical benefit, and no autophagy-modulating therapies have been approved for clinical use.The autophagy process starts with the formation of a double-membrane autophagosome, which engulfs cytoplasmic materials. Autophagosomes are targeted to the lysosomal compartment and single-membrane autolysosomes are generated in which the sequestered cargos are degraded in the highly acidic environment and the resulting simple products are reused (6, 7). There are many molecules involved in autophagy, including Beclin-1 (involved in vesicle nucleation); Atg5, Atg7, and Atg16L1 (involved in vesicle elongation); and LC3 (involved in the expansion of autophagosome membrane and autophagosome-lysosome fusion) (8). Autophagy occurs in almost all cell types, including macrophages. Macrophages primarily use phagocytosis as the first line of defense against exogenous pathogens and endogenous waste products. They adopt autophagy to process bulky materials (e.g., damaged mitochondria and excessive lipids) in unfavorable microenvironments, thus mitigating cytotoxicity. Recently, autophagy has been shown to play a critical role in inflammatory responses in macrophages by interacting with inflammasomes or directly targeting pro-interleukin Abstract Macrophage autophagy has been shown to be protective against atherosclerosis. We previously discovered that ursolic acid (UA) promoted cancer cell autophagy. In the present study, we aimed to examine whether UA enhances macrophage autophagy in the context of atherogenesis. Cell culture study showed that UA enhanced autophagy of macrophages by increasing the expression of Atg5 and Atg16l1, which led to altered macrophage function. UA reduced pro-interleukin (IL)-1 protein levels and mature IL-1 secretion in macrophages in response to lipopolysaccharide (LPS), without reducing IL-1 mRNA expression. Confocal microscopy showed that in LPS-treated macrophages, UA increased LC3 protein levels and LC3 appeared to colocalize with IL-1. In cholesterolloaded macrophages, UA increased cholesterol efflux to apoAI, although it did not alter mRNA or protein levels of ABCA1 and ABCG1. Electron microscopy showed that UA induced lipophagy in acetylated LDL-loaded macrophages, which may result in increased cholesterol ester hydrolysis in autophagolysosomes and presentation of free cholesterol to the cell membrane. In LDLR / mice fed a Western diet to induce atherogenesi...

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Section: Discussionmentioning

confidence: 99%

Section: Mtt Assaymentioning

confidence: 99%

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Leng

Iwanowycz

Saaoud

et al. 2016

Journal of Lipid Research

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“…Chemotaxis assays were conducted in 48-well modified Boyden chamber (NeuroProbe) as described previously (17,45). Briefly, cells were washed and resuspended (1-2 × 10 6 /mL) in THP-1 medium with 0.1% FBS.…”

Section: Methodsmentioning

confidence: 99%

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

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

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101

125

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Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the Sglutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1, 2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3-5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications. Metabolic disorders impact blood vessels at multiple levels, including lipid depositions, endothelial injury, and smooth muscle cell proliferation and migration, which individually or in concert initiate monocyte recruitment and promote vascular inflammation (6, 7). However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8-13)...

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“…With results from various studies that investigated the protective effects of ursolic acid (UA) on inflammation and atherosclerosis, it therefore could be concluded that UA can prevent inflammation and may have positive significance for prevention and treatment of atherosclerosis and other CVD diseases [25][26][27].…”

Section: Page 4 Of 11mentioning

confidence: 99%

Biologically Active Triterpenoids and Their Cardioprotective and Anti- Inflammatory Effects

Bakovic¹

2015

J Bioanal Biomed

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Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis

Cited by 77 publications

References 41 publications

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Biologically Active Triterpenoids and Their Cardioprotective and Anti- Inflammatory Effects

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