Abstract 3444: Arachidonic 12-lipoxygenase Promotes the Development of Cardiac Fibrosis and Heart Failure via Induction of Monocyte Chemoattractant Protein-1

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yosuke Kayama
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
12 Lipoxygenase

To elucidate the molecular mechanisms of heart failure, we examined expression of 8800 genes in the heart of hypertensive heart failure model (Dahl salt-sensitive rats). DNA chip analysis revealed that 12-lipoxygenase (12-LOX) was markedly upregulated in the failing heart. 12-LOX is a key enzyme of the arachidonic cascade that metabolizes eicosanoid. Until recently, 12-LOX has been reported to play an important role in the development of atherogenesis, diabetes, and neurogenerative disease. However, the role of 12-LOX in heart failure has not been examined. To determine whether increased expression of 12-LOX causes heart failure, we established transgenic mice that overexpress 12-LOX only in cardiomyocytes. Echocardiogra-phy showed that 12-LOX transgenic mice developed systolic dysfunction from as early as 16 weeks old. Histological analysis revealed that cardiac fibrosis was increased in 12-LOX transgenic mice with advancing age, which was associated with infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (MCP-1) was upregulated in 12-LOX transgenic mice compared to those of wild-type mice. In vitro experiments demonstrated that treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12-LOX, increased MCP-1 expression in cardiac fibroblast and endothelial cells but not in cardiomyocytes. To determine the role of MCP-1 in the heart of 12LOX transgenic mice, we treated these mice with 7ND, an inhibitor of MCP-1, for 32 weeks. Chronic treatment with 7ND attenuated infiltration of macrophages into the myocardium and prevented systolic dysfunction and cardiac fibrosis in 12-LOX transgenic mice. Likewise, disruption of 12-LOX significantly reduced expression of MCP-1 and infiltration of macrophages in the heart, thereby inhibiting cardiac remodeling after myocardial infarction. Our in vitro and in vivo results suggest that cardiac 12-LOX is critically involved in the development of heart failure and that inhibition of 12-LOX will be a novel target for the treatment of this condition.

scholarly journals Cardiac 12/15 lipoxygenase–induced inflammation is involved in heart failure

2009 ◽  
Vol 206 (7) ◽  
pp. 1565-1574 ◽  
Author(s):  
Yosuke Kayama ◽  
Tohru Minamino ◽  
Haruhiro Toko ◽  
Masaya Sakamoto ◽  
Ippei Shimizu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Eicosatetraenoic Acid ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Target

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

Abstract P771: Monocyte-Chemoattractant Protein-1 Levels in Human Carotid Atherosclerosis Associate With Hallmarks of Plaque Vulnerability

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Marios K Georgakis ◽  
Sander W van der Laan ◽  
Yaw Asare ◽  
Joost M Mekke ◽  
Saskia Haitjema ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Intraplaque Hemorrhage ◽  
Vascular Risk ◽  
Plaque Vulnerability ◽  
Vascular Events ◽  
Monocyte Chemoattractant Protein 1 ◽  
Plaque Instability ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein

Background: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine recruiting monocytes to the atherosclerotic plaque. Experimental, genetic, and epidemiological data support a key role of MCP-1 in atherosclerosis. Yet, the translational potential of targeting MCP-1 signaling for lowering vascular risk is limited by the lack of data on plaque MCP-1 activity in human atherosclerosis. Methods: We measured MCP-1 levels in human plaque samples from 1,199 patients undergoing carotid endarterectomy from the Athero-Express Biobank. We explored associations of plaque MCP-1 levels with histopathological features of plaque vulnerability, clinical plaque instability (symptomatic vs. asymptomatic plaque), molecular markers of plaque inflammation and remodeling, and with incident vascular events up to three years after plaque removal. Results: MCP-1 plaque levels were associated with individual histopathological hallmarks of plaque vulnerability (large lipid core, low collagen, high macrophage burden, low smooth muscle cell burden, intraplaque hemorrhage), as well as with a cumulative vulnerability index (range 0-5, beta: 0.42, 95%CI: 0.30-0.53, p=5.4x10 -13 ) independently of age, sex, and conventional vascular risk factors. Furthermore, MCP-1 levels were higher among patients with symptomatic, as compared to asymptomatic plaques (p=0.0001) and were associated with the levels of pro-inflammatory cytokines involved in leukocyte adhesion, as well as with matrix metalloproteinase activity in the plaque. In the follow-up analyses, MCP-1 levels were associated with a higher risk of peri-procedural events (up to 30 days after surgery). Conclusions: Our findings highlight a role of MCP-1 in human plaque vulnerability, the leading mechanism underlying vascular events like stroke and myocardial infarction. As such, they suggest that interfering with MCP-1 signaling in patients with established atherosclerosis could lower vascular risk.

scholarly journals Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells.

1998 ◽  
Vol 9 (12) ◽  
pp. 2283-2290
Author(s):  
B Beck-Schimmer ◽  
B Oertli ◽  
T Pasch ◽  
R P Wüthrich
Keyword(s):  
Protein Expression ◽  
Renal Injury ◽  
De Novo ◽  
Kidney Diseases ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Mrna And Protein Expression ◽  
Renal Tubular

Hyaluronan (HA) is a nonsulfated glycosaminoglycan that accumulates in the renal interstitium in immune-mediated kidney diseases. The functional significance of such HA deposition in the kidney has not been elucidated. Several studies have suggested that HA may exhibit proinflammatory effects. Since chemokines such as monocyte chemoattractant protein-1 (MCP-1) play an important role in the recruitment of leukocytes in renal injury, this study tested whether HA and its fragments could promote MCP-1 production by renal parenchymal cells. Mouse cortical tubular cells were stimulated with fragmented HA or with high molecular weight HA (Healon) in vitro and were examined for MCP-1 expression. Fragmented HA, but not Healon, increased MCP-1 mRNA within 30 min with a peak after 2 h. In addition, a 10-fold increase of MCP-1 protein in the supernatant was found after a 6-h stimulation with fragmented HA. The enhanced MCP-1 mRNA and protein expression in response to HA was dose-dependent between 1 and 100 microg/ml. Upregulation of MCP-1 protein production could be blocked by preincubation with actinomycin D or cycloheximide, suggesting that MCP-1 mRNA and protein expression in response to HA are based on de novo synthesis. The HA-stimulated MCP-1 production was also inhibited with anti-CD44 antibodies, suggesting that MCP-1 is upregulated at least in part by signaling through CD44. In summary, fragmented HA markedly stimulates renal tubular MCP-1 production by mechanisms that involve binding to the HA receptor CD44. It is hypothesized that the accumulation of HA in immune renal injury could participate in the recruitment and activation of inflammatory cells in vivo through production of MCP-1.

scholarly journals Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) Drives Activation of Bone Remodelling and Skeletal Metastasis

2019 ◽  
Vol 17 (6) ◽  
pp. 538-547 ◽  
Author(s):  
Bridie S. Mulholland ◽  
Mark R. Forwood ◽  
Nigel A. Morrison
Keyword(s):  
Breast Cancer Cells ◽  
Bone Remodelling ◽  
Skeletal Metastasis ◽  
Osteoclast Formation ◽  
Intermittent Treatment ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Prostate Cancers

Abstract Purpose of Review The purpose of this review is to explore the role of monocyte chemoattractant protein-1 (MCP-1 or CCL2) in the processes that underpin bone remodelling, particularly the action of osteoblasts and osteoclasts, and its role in the development and metastasis of cancers that target the bone. Recent Findings MCP-1 is a key mediator of osteoclastogenesis, being the highest induced gene during intermittent treatment with parathyroid hormone (iPTH), but also regulates catabolic effects of continuous PTH on bone including monocyte and macrophage recruitment, osteoclast formation and bone resorption. In concert with PTH-related protein (PTHrP), MCP-1 mediates the interaction between tumour-derived factors and host-derived chemokines to promote skeletal metastasis. In breast and prostate cancers, an osteolytic cascade is driven by tumour cell–derived PTHrP that upregulates MCP-1 in osteoblastic cells. This relationship between PTHrP and osteoblastic expression of MCP-1 may drive the colonisation of disseminated breast cancer cells in the bone. Summary There is mounting evidence to suggest a pivotal role of MCP-1 in many diseases and an important role in the establishment of comorbidities. Coupled with its role in bone remodelling and the regulation of bone turnover, there is the potential for pathological relationships between bone disorders and bone-related cancers driven by MCP-1. MCP-1’s role in bone remodelling and bone-related cancers highlights its potential as a novel anti-resorptive and anti-metastatic target.

scholarly journals C–C motif chemokine receptor 2 as a novel intermediate in the ovulatory cascade

2020 ◽  
Vol 26 (5) ◽  
pp. 289-300
Author(s):  
JP Jaworski ◽  
M Urrutia ◽  
E Dascal ◽  
G Jaita ◽  
MC Peluffo
Keyword(s):  
Oocyte Maturation ◽  
Chemokine Receptor ◽  
Follicle Cells ◽  
Mrna Levels ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Cumulus Oocyte Complex ◽  
Key Genes

Abstract Expression of immune function genes within follicle cells has been reported in ovaries from many species. Recent work from our laboratory showed a direct effect of the monocyte chemoattractant protein 1/C-C motif chemokine receptor 2 system within the feline cumulus oocyte complex, by increasing the mRNA levels of key genes involved in the ovulatory cascade in vitro. Studies were designed to evaluate if C–C motif chemokine receptor 2 acts as a novel mediator of the ovulatory cascade in vitro. Therefore, feline cumulus oocyte complexes were cultured in the presence or absence of a highly selective C–C motif chemokine receptor 2 antagonist together with known inducers of cumulus–oocyte expansion and/or oocyte maturation to assess mRNA expression of key genes related to periovulatory events in other species as well as oocyte maturation. Also, the effects of recombinant monocyte chemoattractant protein 1 on spontaneous or gonadotrophin-induced oocyte maturation were assessed. This is an in vitro system using isolated cumulus oocyte complexes from feline ovaries. The present study reveals the modulation of several key ovulatory genes by a highly selective C–C motif chemokine receptor 2 antagonist. However, this antagonist was not enough to block the oocyte maturation induced by gonadotropins or amphiregulin. Nonetheless, recombinant monocyte chemoattractant protein 1 had a significant effect on spontaneous oocyte maturation, increasing the percentage of metaphase II stage oocytes in comparison to the control. This is the first study in any species to establish C–C motif chemokine receptor 2 as a mediator of some actions of the mid-cycle gonadotrophin surge.

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