scholarly journals C1q/TNF-Related Protein 9 Attenuates Atherosclerosis by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the AMPKα/KLF4 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Gang Wang ◽  
Baihe Han ◽  
Ruoxi Zhang ◽  
Qi Liu ◽  
Xuedong Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Plaque Formation ◽  
Cell Senescence ◽  
Related Protein ◽  
Atherosclerotic Plaque Formation ◽  
Apoe Ko Mice ◽  
Apoe Ko

Hyperglycemia-induced endothelial cell senescence has been widely reported to be involved in the pathogenesis of type 2 diabetes mellitus‒accelerated atherosclerosis. Thus, understanding the underlying mechanisms and identifying potential therapeutic targets for endothelial cell senescence are valuable for attenuating atherosclerosis progression. C1q/tumor necrosis factor-related protein 9 (CTRP9), an emerging potential cardiokine, exerts a significant protective effect with respect to atherosclerosis, particularly in endothelial cells. However, the exact mechanism by which CTRP9 prevents endothelial cells from hyperglycemia-induced senescence remains unclear. This study aimed to investigate the effects of CTRP9 on hyperglycemia-induced endothelial cell senescence and atherosclerotic plaque formation in diabetic apolipoprotein E knockout (ApoE KO) mice. Human umbilical vein endothelial cells (HUVECs) were cultured in normal glucose (5.5 mM) and high glucose (40 mM) with or without recombinant human CTRP9 protein (3 μg/ml) for 48 h. Purified lentiviruses overexpressing CTRP9 (Lv-CTRP9) and control vectors containing green fluorescent protein (Lv-GFP) were injected via the tail vein into streptozotocin-induced diabetic ApoE KO mice. Results revealed that exposure of HUVECs to HG significantly increased the expression of Krüppel-like factor 4 (KLF4) and cyclin-dependent kinase inhibitor p21 (p21) and decreased that of telomerase reverse transcriptase (TERT). Treatment with recombinant human CTRP9 protein protected HUVECs from HG-induced premature senescence and dysfunction. CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), attenuated the expression of KLF4 and p21 induced by HG, and increased the expression of TERT in HUVECs. Furthermore, in the background of AMPKα knockdown or KLF4 activation, the protective effects of CTRP9 were abolished. In-vivo experiments showed that the overexpression of CTRP9 inhibited vascular senescence and reduced atherosclerotic plaque formation in ApoE KO mice with diabetes. In conclusion, we demonstrate that KLF4 upregulation plays a crucial role in HG-induced endothelial senescence. This anti-atherosclerotic effect of CTRP9 may be partly attributed to the inhibition of HG-induced endothelial senescence through an AMPKα/KLF4-dependent mechanism, suggesting that CTRP9 could benefit further therapeutic approaches for type 2 diabetes mellitus‒accelerated atherosclerosis.

scholarly journals Hyperglycemia and Endothelial Dysfunction in Atherosclerosis: Lessons from Type 1 Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Steven Daniel Funk ◽  
Arif Yurdagul ◽  
A. Wayne Orr
Keyword(s):  
Endothelial Cell ◽  
Cell Biology ◽  
Plaque Formation ◽  
Multiple Components ◽  
Vessel Permeability ◽  
Cell Culture Systems ◽  
Type 2 Diabetics ◽  
Atherosclerotic Plaque Formation

A clear relationship between diabetes and cardiovascular disease has been established for decades. Despite this, the mechanisms by which diabetes contributes to plaque formation remain in question. Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes. However, the hyperglycemia that defines the diabetic condition independently affects atherogenesis in cell culture systems, animal models, and human patients. Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis. The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation.

Abstract 5492: Tetrahydrobiopterin (BH4) Improves Endothelial Cell Survival After Vascular Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruth Rinze ◽  
Ziad A Ali ◽  
Gillian Douglas ◽  
Nicholas J Alp ◽  
Keith M Channon
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Vascular Injury ◽  
Neointimal Hyperplasia ◽  
Wild Type ◽  
Endothelial Cell Survival ◽  
Apoe Ko Mice ◽  
Apoe Ko

Endothelial cell loss, survival and regeneration are important aspects of the response to vascular injury leading to neointimal hyperplasia and accelerated atherosclerosis. Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a key regulator of endothelial cell biology and has been shown to prevent endothelial cell apoptosis. The cofactor tetrahydrobiopterin (BH4) is essential for eNOS catalytic activity but its impact on endothelial cell survival and regeneration remains unclear. We investigated the effect of BH4 on endothelial cell survival and vascular remodelling using ApoE-KO mice with transgenic endothelial-targeted overexpression of GTP cyclohydrolase 1 (GCH), the rate limiting enzyme of BH4 synthesis, and with endothelial specific transgenic expression of the LacZ reporter gene. Using venous bypass grafts as an in vivo model of acute vascular injury, we observed that endothelial-specific augmentation of BH4 in GCH/ApoE-KO mice improved survival of vein graft-derived endothelial cells and reduced neointimal hyperplasia. To address the hypothesis that augmentation of BH4 increases the capacity of endothelial cells from GCH/ApoE-KO mice to survive vascular injury, we cultured primary lung endothelial cells from mice expressing the GCH transgene and wild type littermates. Endothelial cells, isolated by immunomagnetic beads, were positive for CD31, CD102 and Tie2. Protein levels of eNOS were not different between wild type and GCH mice. BH4 levels were selectively increased in pulmonary endothelial cells from GCH mice, > 10-fold, compared with a 3-fold increase in total lung tissue BH4. There was no difference in total lung endothelial cell content or amount of isolated cells between ApoE-KO and GCH/ApoE-KO mice, determined by Tie2-driven β-galactosidase activity. However, after 3 days of culture both total endothelial cell number and number of endothelial cell colonies in GCH/ApoE-KO were significantly increased (236% ± 47 p=0.028 and 195% ± 28 p=0.014 respectively, n=5) whereas mean colony size remained unchanged. These observations indicate an important role for BH4 in endothelial cell survival and endothelial regeneration, and identify BH4 as a potential therapeutic target in vascular injury states.

scholarly journals Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Zhu Zhu ◽  
Bingxuan Hua ◽  
Zhanxian Shang ◽  
Gongsheng Yuan ◽  
Lirong Xu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Serum Lipids ◽  
Clock Genes ◽  
Plaque Formation ◽  
Sirtuin 1 ◽  
Atheromatous Plaque ◽  
Circadian Oscillation ◽  
Lighting Condition ◽  
Apoe Ko Mice ◽  
Apoe Ko

Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice.Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity.Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice.Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

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.

scholarly journals C1q/TNF-related protein-9 attenuates palmitic acid-induced endothelial cell senescence via increasing autophagy

2021 ◽  
Vol 521 ◽  
pp. 111114
Author(s):  
Jiwoo Lee ◽  
Jee Hee Yoo ◽  
Hwi Seung Kim ◽  
Yun Kyung Cho ◽  
Yoo La Lee ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Palmitic Acid ◽  
Cell Senescence ◽  
Related Protein

scholarly journals Interleukin-37: The Effect of Anti-Inflammatory Response in Human Coronary Artery Endothelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Xianfeng Yan ◽  
Bin Xie ◽  
Guihai Wu ◽  
Jing Hu ◽  
Di Wang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Inflammatory Response ◽  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Plaque Formation ◽  
Human Coronary Artery ◽  
Atherosclerotic Plaque Formation

Interleukin-37 (IL-37) is unique in the IL-1 family since it broadly suppresses innate immunity and elevates in humans with inflammatory and autoimmune diseases. IL-37 shows definite groups and transcripts for human IL37 gene, but it is still not completely understood the effect and mechanisms of inflammatory response in endothelial cells. It is well accepted that endothelial dysfunction caused by inflammation is a key initiating event in atherosclerotic plaque formation, which leads to the occurrence and development of the cardiovascular adverse events in clinical since the inflammatory responses of endothelial cells could induce and enhance the deposition of extensive lipid and the formation of atherosclerotic plaque in the intima. Thus, it is essential to investigate the role and potential mechanisms in endothelial inflammatory response to prevent the formation and development of many cardiovascular diseases including atherosclerosis. So far, the recent studies have revealed that IL-37 is able to inhibit inflammatory response by suppressing the TLR2-NF-κB-ICAM-1 pathway intracellularly in human coronary artery endothelial cells (HCAECs). Further, the role of IL-37 may be related to the IL-18 pathway extracellularly and involved in the adhesion and transmigration of neutrophils in HCAECs.

scholarly journals Serum IL-6 and sIL-6R in type 2 diabetes contribute to impaired capillary-like network formation

2019 ◽  
Vol 127 (2) ◽  
pp. 385-392
Author(s):  
Rian Q. Landers-Ramos ◽  
Jacob B. Blumenthal ◽  
Steven J. Prior
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Glucose Tolerance ◽  
Interleukin 6 ◽  
Network Formation ◽  
Normal Glucose Tolerance ◽  
Normal Glucose

We hypothesized that the serum from individuals with type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) would reduce in vitro capillary-like network formation compared with normal glucose tolerance (NGT) serum and that this would occur along with higher serum concentrations of inflammatory cytokines and lower concentrations of angiogenic growth factors. Subjects were sedentary, older (55–65 yr) adults with NGT, IGT, or T2DM ( n = 10/group) matched for body mass index. Human retroviral telomerized endothelial cells (HRVT-ECs) or coronary artery endothelial cells (CECs) were used in a capillary-like network formation assay using endothelial basal medium supplemented with 7.5% serum. Quantification of HRVT-EC network length indicated that serum from the T2DM group resulted in 32 and 35% lower network formation than when using serum from the NGT and IGT groups, respectively ( P < 0.05). Serum from T2DM subjects resulted in CEC network formation that was 11 and 8% lower than when using serum from NGT and IGT subjects, respectively ( P < 0.05). Analysis of serum cytokines indicated that IL-6 was 41% and 49% higher in the IGT and T2DM groups, respectively, compared with the NGT group ( P < 0.05) and there was a trend for higher soluble interleukin-6 receptor (sIL-6R; P = 0.06) and IL-8 ( P = 0.08) in the T2DM serum compared with NGT. The use of recombinant IL-6 and sIL-6R at concentrations detected in the T2DM serum also reduced capillary network formation compared with NGT concentrations ( P < 0.05). These results suggest that IL-6 and sIL-6R present in the serum of T2DM individuals impair in vitro endothelial cell function across different cell lines. Our findings may have implications for the microvascular complications associated with T2DM. NEW & NOTEWORTHY Higher concentrations of serum factors, specifically Interleukin-6 and its soluble receptor found in individuals with type 2 diabetes (T2DM) appear to impair endothelial cell capillary-like network formation compared with those present in serum from individuals with impaired glucose tolerance and normal glucose tolerance. This may have implications for the vascular complications associated with T2DM.

scholarly journals Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis

2000 ◽  
Vol 346 (3) ◽  
pp. 603-610 ◽  
Author(s):  
Injune KIM ◽  
Hwan-Gyu KIM ◽  
Hyun KIM ◽  
Hong-Hee KIM ◽  
Sung Kwang PARK ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Signal Sequence ◽  
Glycosylation Site ◽  
Related Protein ◽  
Hydrophobic Region ◽  
Protective Function ◽  
Hepatic Expression ◽  
Mouse Tissues ◽  
Human And Mouse

Using degenerate PCR we isolated a cDNA encoding a novel 406- and 410-amino acid protein from human and mouse embryonic cDNAs and have designated it ‘hepatic fibrinogen/angiopoietin-related protein’ (HFARP). The N-terminal and C-terminal portions of HFARP contain the characteristic coiled-coil domains and fibrinogen-like domains that are conserved in angiopoietins. In human and mouse tissues, HFARP mRNA is specifically expressed in the liver. HFARP mRNA and protein are mainly present in the hepatocytes. HFARP has a highly hydrophobic region at the N-terminus that is typical of a secretory signal sequence and one consensus glycosylation site. Recombinant HFARP expressed in COS-7 cells is secreted and glycosylated. HFARP protein is present not only in the hepatocytes, but also in the circulating blood. Recombinant HFARP acts as an apoptosis survival factor for vascular endothelial cells, but does not bind to Tie1 or Tie2 (endothelial-cell tyrosine kinase receptors). These results suggest that HFARP may exert a protective function on endothelial cells through an endocrine action.

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