Smooth Muscle-specific Expression of Calcium-independent Phospholipase A2β (iPLA2β) Participates in the Initiation and Early Progression of Vascular Inflammation and Neointima Formation

Liu, Shu; Xie, Zhongwen; Zhao, Qiu; Pang, Huan; Turk, John; Calderon, Lindsay E.; Su, Wen; Zhao, Guogang; Xu, Haowen; Gong, Ming; Guo, Zhenheng

doi:10.1074/jbc.m112.340216

Cited by 23 publications

(21 citation statements)

References 53 publications

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“…In contrast, increases in iPLA 2 β activity are associated with myocardial ischemia, 57 cancer (reviewed in ref. 9) and inflammatory responses 58 - 60 . Of importance to our findings, increases in iPLA 2 β activity (human neutrophils, and rodent myocardium and vascular smooth muscle) 61 - 63 have been reported in T1DM.…”

Section: Discussionsupporting

confidence: 68%

Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy

Lei

Bone

Ali

et al. 2013

Islets

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β-cell apoptosis is a significant contributor to β-cell dysfunction in diabetes and ER stress is among the factors that contributes to β-cell death. We previously identified that the Ca2+-independent phospholipase A2β (iPLA2β), which in islets is localized in β-cells, participates in ER stress-induced β-cell apoptosis. Here, direct assessment of iPLA2β role was made using β-cell-specific iPLA2β overexpressing (RIP-iPLA2β-Tg) and globally iPLA2β-deficient (iPLA2β-KO) mice. Islets from Tg, but not KO, express higher islet iPLA2β and neutral sphingomyelinase, decrease in sphingomyelins, and increase in ceramides, relative to WT group. ER stress induces iPLA2β, ER stress factors, loss of mitochondrial membrane potential (∆Ψ), caspase-3 activation, and β-cell apoptosis in the WT and these are all amplified in the Tg group. Surprisingly, β-cells apoptosis while reduced in the KO is higher than in the WT group. This, however, was not accompanied by greater caspase-3 activation but with larger loss of ∆Ψ, suggesting that iPLA2β deficiency impacts mitochondrial membrane integrity and causes apoptosis by a caspase-independent manner. Further, autophagy, as reflected by LC3-II accumulation, is increased in Tg and decreased in KO, relative to WT. Our findings suggest that (1) iPLA2β impacts upstream (UPR) and downstream (ceramide generation and mitochondrial) pathways in β-cells and (2) both over- or under-expression of iPLA2β is deleterious to the β-cells. Further, we present for the first time evidence for potential regulation of autophagy by iPLA2β in islet β-cells. These findings support the hypothesis that iPLA2β induction under stress, as in diabetes, is a key component to amplifying β-cell death processes.

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Section: Discussionsupporting

confidence: 68%

Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy

Lei

Bone

Ali

et al. 2013

Islets

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“…In addition, secretory smooth muscle cells synthesize and secrete high levels of various cytokines and adhesion molecules, which promote the early occurrence of local inflammatory reactions of the damaged vessel and form an extremely complicated inflammation network control system via the sequential activation of multiple overlapping intracellular signal pathways. Moreover, this process causes the chemotaxis of inflammatory cells and inflammatory cell aggregation and adhesion, aggravates inflammatory reactions, induces local lesion of the vessel, and promotes postintervention restenosis [34,35]. Therefore, further research on inflammation-activated smooth muscle cells is important for the prevention and treatment of restenosis.…”

Section: Discussionmentioning

confidence: 99%

Effect of Paclitaxel+Hirudin on the TLR4-MyD88 Signaling Pathway During Inflammatory Activation of Human Coronary Artery Smooth Muscle Cells and Mechanistic Analysis

Li¹,

Wang²,

Xu³

2018

Cell Physiol Biochem

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Background/Aims: Approximately 10%-20% of patients with acute cardiovascular disease who have received coronary intervention suffer restenosis and high inflammation. The stent compound paclitaxel+hirudin was prepared for the treatment of post-intervention restenosis. This study aimed to explore the anti-inflammatory and anti-restenosis mechanisms of paclitaxel+hirudin with regard to the TLR4/MyD88/NF-κB pathway. Methods: Human coronary artery smooth muscle cells (HCASMCs) at 4-6 generations after in vitro culture were used as a model. Lipopolysaccharide (LPS) was used as an inducer to maximally activate the TLR4/MyD88/NF-κB inflammation pathway. After MyD88 knockdown and selective blocking of MyD88 degradation with epoxomicin, the effects of paclitaxel+hirudin stenting on key sites of the TLR4/MyD88/NF-κB pathway were detected using ELISA, Q-PCR, and western blot analysis. Results: LPS at 1 μg/mL for 48 h was the optimal modeling condition for inflammatory activation of HCASMCs. Paclitaxel+hirudin inhibited the levels of key proteins and the gene expression, except for that of the MyD88 gene, of the TLR4-MyD88 pathway. The trend of the effect of paclitaxel+hirudin on the pathway proteins was similar to that of MyD88 knockdown. After epoxomicin intervention, the inhibitory effects of paclitaxel+hirudin on the key genes and proteins of the TLR4-MyD88 pathway were significantly weakened, which even reached pre-intervention levels. Paclitaxel+hirudin affected the MyD88 protein in a dosage-dependent manner. Conclusion: The paclitaxel+hirudin compound promotes MyD88 degradation in the TLR4/MyD88/NF-κB pathway to reduce the activity of TLR4 and NF-κB p65 and to weaken the LPS-initiated inflammatory reactions of IL-1β, IL-6, and TNF-α.

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“…Conversely, overexpression of Ca 2+ -independent PLA2-β led to increased vascular inflammation in a vascular ligation model in mice. 20 In addition to the release of arachidonic acid, activation of PLA2 results in the production of LPC. Generation of LPC via activation of the Ca 2+ -independent PLA2 and exposure of LPC on the cell surface is a mechanism generally identified in activated or apoptotic cells.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

et al. 2014

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Recent animal work has suggested that injection of human pCRP can increase myocardial infarct size in a rat myocardial Background-The relevance of the dissociation of circulating pentameric C-reactive protein (pCRP) to its monomeric subunits (mCRP) is poorly understood. We investigated the role of conformational C-reactive protein changes in vivo. Methods and Results-We identified mCRP in inflamed human striated muscle, human atherosclerotic plaque, and infarcted myocardium (rat and human) and its colocalization with inflammatory cells, which suggests a general causal role of mCRP in inflammation. This was confirmed in rat intravital microscopy of lipopolysaccharide-induced cremasteric muscle inflammation. Intravenous pCRP administration significantly enhanced leukocyte rolling, adhesion, and transmigration via localized dissociation to mCRP in inflamed but not noninflamed cremaster muscle. This was confirmed in a rat model of myocardial infarction. Mechanistically, this process was dependent on exposure of lysophosphatidylcholine on activated cell membranes, which is generated after phospholipase A2 activation. These membrane changes could be visualized intravitally on endothelial cells, as could the colocalized mCRP generation. Blocking of phospholipase A2 abrogated C-reactive protein dissociation and thereby blunted the proinflammatory effects of C-reactive protein.Identifying the dissociation process as a therapeutic target, we stabilized pCRP using 1,6-bis(phosphocholine)-hexane, which prevented dissociation in vitro and in vivo and consequently inhibited the generation and proinflammatory activity of mCRP; notably, it also inhibited mCRP deposition and inflammation in rat myocardial infarction. Conclusions-These results provide in vivo evidence for a novel mechanism that localizes and aggravates inflammation via phospholipase A2-dependent dissociation of circulating pCRP to mCRP. mCRP is proposed as a pathogenic factor in atherosclerosis and myocardial infarction. Most importantly, the inhibition of pCRP dissociation represents a promising, novel anti-inflammatory therapeutic strategy. (Circulation. 2014;130:35-50.)

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Smooth Muscle-specific Expression of Calcium-independent Phospholipase A2β (iPLA2β) Participates in the Initiation and Early Progression of Vascular Inflammation and Neointima Formation

Cited by 23 publications

References 53 publications

Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy

Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy

Effect of Paclitaxel+Hirudin on the TLR4-MyD88 Signaling Pathway During Inflammatory Activation of Human Coronary Artery Smooth Muscle Cells and Mechanistic Analysis

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

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Smooth Muscle-specific Expression of Calcium-independent Phospholipase A2β (iPLA2β) Participates in the Initiation and Early Progression of Vascular Inflammation and Neointima Formation

Cited by 23 publications

References 53 publications

Genetic modulation of islet β-cell iPLA2β expression provides evidence for its impact on β-cell apoptosis and autophagy

Genetic modulation of islet β-cell iPLA2β expression provides evidence for its impact on β-cell apoptosis and autophagy

Effect of Paclitaxel+Hirudin on the TLR4-MyD88 Signaling Pathway During Inflammatory Activation of Human Coronary Artery Smooth Muscle Cells and Mechanistic Analysis

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

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Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy

Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy