Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic <i>db/db</i> Mice

Li, Shu Iian; Reddy, Marpadga A.; Cai, Qiangjun; Li, Meng; Yuan, Hang; Lanting, Linda; Natarajan, Rama

doi:10.2337/db06-0164

Cited by 113 publications

(108 citation statements)

References 56 publications

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“…48 Increased expression of arginase-1 and IL-10 in db/db macrophages, compared with db/ϩ macrophages, may be an adaptive response under the stress of diabetes. 49 The DHA-derived lipid mediator 14S,21R-diHDHA acts as an macrophage-produced autacoid that promotes the prohealing functions of macrophages ( Figure 7). Reduced formation of 14S,21R-diHDHA in db/db macrophages is associated with their impaired prohealing functions.…”

Section: Discussionmentioning

confidence: 99%

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S, 2 1 R -d i h y d r o x y d o c o s a -4 Z , 7Z , 1 0 Z , 1 2 E , 1 6 Z , 19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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“…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)(9)(10)(11)(12)(13).…”

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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.

104

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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“…39) The activation of pro-inflammatory factors in VSMC and other inflammatory cells, including cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), receptors of advanced glycation end products (RAGE), interleukin-6 (IL-6), Fractalkine (CX3CL1), and MCP-1, was enhanced by diabetes. 35,40) It was shown that the activation of COX-2 and MCP-1 promoters by miR-135a was inhibited by transcription factor FOXO1, suggesting the repressive transcription factors at the promoters of pro-inflammatory genes are involved in an underlying mechanism for elevated expression of inflammatory genes mediated by miR135a in VSMC.…”

Section: Discussionmentioning

confidence: 99%

“…Ex vivo and in vitro studies showed that CX3CL1 and MCP-1, whose expression was elevated under diabetic conditions, promote monocyte-VSMC binding and the formation of foam cells, both of which are critical events during the onset of atherosclerosis. 35) Therefore, the control of inflammatory genes, including COX-2 and MCP-1, by miR-135a-FOXO1 could further aid the binding of monocytes and their differentiation, thus resulting in more serious vascular complications. Other studies have shown that the increased level of COX-2 in db/db VSMC was also related to the hypercontractility of vascular smooth muscle during hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that as compared to control WT VSMC, MCP-1 induced increased monocyte binding in db/db VSMC. 35) However, the role of increased COX-2 is not known yet. In this study, it was first confirmed that as compared to the WT VSMC, both COX-2 mRNA ( Figure 4A) and COX-2 mRNA protein ( Figure 4B, C) levels were greatly elevated in db/db.…”

Section: Mir-135a Increases the Level Of Inflammatory Genesmentioning

confidence: 99%

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MiR-135a Promotes Inflammatory Responses of Vascular Smooth Muscle Cells From db/db Mice via Downregulation of FOXO1

Yin

Zhou

et al. 2018

Int. Heart J.

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SummaryIt has been shown that microRNAs (miRNAs) greatly affect the functions of vascular smooth muscle cells (VSMC), but the effects of mRNAs under diabetic conditions remain unclear.Using a model of diabetic db/db mice, we studied the functions of microRNA-135a (miR-135a) during VSMC dysfunction.Compared to control WT mice, miR-135a expression in VSMC was significantly increased while the level of forkhead box O1 (FOXO1) protein decreased significantly. After transfecting miR-135a mimics into VSMC, the expression of FOXO1 was decreased, while cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression levels were increased, thus promoting the interaction between monocytes and WT VSMC. On the other hand, transfection of an miR-135a inhibitor reversed the activated interaction between monocytes and db/db VSMC. The pro-inflammatory responses could also be enhanced by using siRNAs to silence the FOXO1 gene in WT VSMC, suggesting a negative regulatory role of FOXO1. FOXO1 siRNAs and miR-135a mimics could both enhance the transcriptional activity of COX-2 promoter. Using chromatin immunoprecipitation, we found that in db/db VSMC, the occupancy in promoter regions of inflammatory genes by FOXO1 was reduced.miR-135a increased the inflammatory responses of VSMC involved in complications of vascular diseases by downregulating the expression of FOXO1.(Int Heart J 2018; 59: 170-179)

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Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

Cited by 113 publications

References 56 publications

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

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

MiR-135a Promotes Inflammatory Responses of Vascular Smooth Muscle Cells From db/db Mice via Downregulation of FOXO1

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