scholarly journals The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice

2010 ◽  
Vol 299 (3) ◽  
pp. H605-H612 ◽  
Author(s):  
Xiuping Chen ◽  
Hanrui Zhang ◽  
Steve McAfee ◽  
Cuihua Zhang
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Sodium Nitroprusside ◽  
Oxidized Ldl ◽  
Reciprocal Relationship ◽  
Reciprocal Regulation ◽  
Tnf Α ◽  
Ldl Uptake ◽  
Apoe Ko Mice ◽  
Apoe Ko

We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 μg·day−1·mouse−1 sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 μg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-α incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-α-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-κB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-κB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.

Abstract 911: Lacking SOCS3 Gene in Macrophages Prevents the Development of Atherosclerosis in ApoE Deficient Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tomoka Yamamoto ◽  
Hideo Yasukawa ◽  
Mitsuhisa Koga ◽  
Yusuke Sugi ◽  
Daisuke Fukui ◽  
...  
Keyword(s):  
Western Blot ◽  
Immunohistochemical Staining ◽  
Oxidized Ldl ◽  
Enzyme Linked Immunosorbent Assay ◽  
Wild Type ◽  
Stat3 Signaling ◽  
Ldl Uptake ◽  
Apoe Ko Mice ◽  
Deficient Mice ◽  
Apoe Ko

Background : Atherosclerosis is now generally accepted as a chronic inflammatory disease characterized by accumulation of blood-derived macrophages in the arterial wall. It has been shown that suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of interleukin-6 (IL-6)-STAT3 signaling that plays an essential role in inflammatory response. In the present study, we determined whether STAT3-mediated IL-6 signaling and SOCS3 within the macrophages would play an important role in the development of atherosclerosis. Methods and Results : We examined the activation of STAT3 and expressions of IL-6 family cytokines and SOCS3 in the aorta of apolipoprotein E knockout mice (ApoE-KO) and control mice by western blot, immunohistochemical staining and RT-PCR. Western blot revealed that STAT3 is phosphorylated in the atherosclerotic lesions from ApoE-KO mice but not in those from control mice. Dual immunohistochemical staining revealed that phosphorylated STAT3 and macrophage marker, MOMA2, were co-expressed in the atherosclerotic plaque in ApoE-KO deficient mice, suggesting that the STAT3 signaling pathway within the macrophages was activated in atherosclerosis. Next, to investigate the role of STAT3-mediated IL-6 signaling and SOCS3 in macrophages during atherogenesis, we created ApoE-KO mice with a macrophage-restricted deletion of SOCS3 gene (ApoE/SOCS3-KO). We found that atherosclerotic lesion area by oil-red O staining was significantly reduced in ApoE/SOCS3-KO (n=17) compared with control ApoE-KO mice (n=13) (4.63±0.43 vs. 8.29±0.50 %, p<0.01). In in vitro analyses, enzyme-linked immunosorbent assay revealed that LPS-induced TNF-alpha production were significantly smaller in SOCS3 deficient macrophages compared with wild type macrophages (n=8, 2238±155 vs. 992±83 pg/ml, p<0.01). Also we found that IL-6-induced oxidized-LDL uptake was 42% reduced in SOCS3 deficient macrophages compared with wild type macrophages (p<0.01). Conclusion: Our data show that the deletion of SOCS3 in macrophages prevents the development of atherosclerosis in mice, possibly by inhibiting the inflammatory cytokine production and oxidized-LDL uptake in macrophages.

Abstract 166: Endothelial Overexpression of LOX-1 Increases Stroke Size in vivo

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Alexander Akhmedov ◽  
Remo D Spescha ◽  
Francesco Paneni ◽  
Giovani G Camici ◽  
Thomas F Luescher
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Dysfunction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Oxidized Ldl ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background— Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model. Methods and Results— 12-week-old male LOX-1TG generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury. LOX-1TG mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7, p < 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover, LOX-1TG showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7, p < 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12, p < 0.05) - two experimental physiological tests for neurological function. Conclusions— Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such LOX-1 -associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.

Tetrahydrobiopterin Slows the Progression of Atherosclerosis

Pteridines ◽  
2007 ◽  
Vol 18 (1) ◽  
pp. 115-121
Author(s):  
Suzuki Kunihiro ◽  
Yoshiyuki Hattori ◽  
Teruo Jojima ◽  
Atsuko Tomizawa ◽  
Toshie Okayasu ◽  
...  
Keyword(s):  
Drinking Water ◽  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Oral Administration ◽  
Mrna Expression ◽  
Inflammatory Factors ◽  
Apoe Ko Mice ◽  
Progression Of Atherosclerosis ◽  
Apoe Ko

Abstract We investigated whether oral tetrahydrobiopterin (BH4) treatment might slow the progression of atherosclerosis using hypercholesterolemic ApoE-knockout (KO) mice. We report that ingesting BH4 in drinking water is effective to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of ApoE-KO mice. Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring NO-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

H2 inhibits TNF-α-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor κB activation in endothelial cells

2011 ◽  
Vol 33 (9) ◽  
pp. 1715-1722 ◽  
Author(s):  
Guohua Song ◽  
Hua Tian ◽  
Jia Liu ◽  
Hongle Zhang ◽  
Xuejun Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Tnf Α

scholarly journals KLF2 is a therapeutic target for COVID-19 induced endothelial dysfunction

2021 ◽  
Author(s):  
Suowen Xu ◽  
Sihui Luo ◽  
Xueying Zheng ◽  
Jianping Weng
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
Cardiovascular Complications ◽  
Monocyte Adhesion ◽  
Sequencing Data ◽  
Atorvastatin Treatment ◽  
Tnf Α ◽  
Adhesive Molecules ◽  
Umbilical Vein Endothelial Cells

AbstractCoronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its mechanism being incompletely understood. Emerging evidence has demonstrated that the endothelium represents the Achilles' heel in COVID-19 patients and that endothelial dysfunction precipitates COVID-19 and accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. Primary human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) were treated with serum from control subjects or COVID-19 patients. Downstream monocyte adhesion and associated gene/protein expression was evaluated in endothelial cells exposed to COVID-19 patient serum in the presence of KLF2 activator (Atorvastatin) or KLF2 overexpression by an adenoviral vector. Here, we demonstrate that the expression of KLF2 was significantly reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines observed in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis and reduced angiogenesis). Treatment of HPMECs with atorvastatin or KLF2 adenovirus ameliorate COVID-19 serum-induced increase in endothelial inflammation and monocyte adhesion by increasing KLF2 expression. Altogether, the present study demonstrates that genetic and pharmacological activation of KLF2 represses COVID-19 associated endothelial dysfunction, heralding a potentially new direction to treat endothelialitis accompanying COVID-19.

scholarly journals C-Reactive Protein Induces Release of Both Endothelial Microparticles and Circulating Endothelial Cells In Vitro and In Vivo: Further Evidence of Endothelial Dysfunction

2011 ◽  
Vol 57 (12) ◽  
pp. 1757-1761 ◽  
Author(s):  
Sridevi Devaraj ◽  
Pappanaicken R Kumaresan ◽  
Ishwarlal Jialal
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Oxidized Ldl ◽  
Circulating Endothelial Cells ◽  
Early Event ◽  
C Reactive Protein ◽  
Endothelial Microparticles ◽  
Reactive Protein

BACKGROUND Inflammation is pivotal in atherosclerosis. A key early event in atherosclerosis is endothelial dysfunction. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a risk marker for cardiovascular disease, and there is mounting evidence to support its role in atherothrombosis. CRP has been shown to promote endothelial dysfunction both in vitro and in vivo. Emerging biomarkers of endothelial dysfunction include circulating endothelial cells (CECs) and endothelial microparticles (EMPs). However, there is a paucity of data examining the effect of CRP on CEC and EMP production in vitro and in vivo. METHODS In this report, we treated human aortic endothelial cells (HAECs) with increasing concentrations of CRP (0–50 μg/mL) or boiled CRP. We counted CECs and EMPs by flow cytometry. RESULTS Although CRP treatment resulted in a significant increase in release of both CECs and EMPs, boiled CRP failed to have an effect. Pretreatment of HAECs with sepiapterin or diethylenetriamine NONOate, both of which preserve nitric oxide (NO), resulted in attenuation of CRP's effects on CECs and EMPs. CD32 and CD64 blocking antibodies but not CD16 antibody or lectin-like oxidized LDL receptor 1 small interfering RNA (LOX-1 siRNA) prevented CRP-induced production of CECs and EMPs. Furthermore, delivery of human CRP to Wistar rats compared with human serum albumin resulted in significantly increased CECs and EMPs, corroborating the in vitro findings. CONCLUSIONS We provide novel data that CRP, via NO deficiency, promotes endothelial dysfunction by inducing release of CECs and EMPs, which are biomarkers of endothelial dysfunction.

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