Abstract 13736: Elimination of Senescent Cells Targeting Senescence Associated Glycoprotein (sagp) Improved the Atherosclerosis and Diabetes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masayoshi Suda ◽  
Ippei Shimizu ◽  
Goro Katsuumi ◽  
Yohko Yoshida ◽  
Yuka Hayashi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cellular Senescence ◽  
Diphtheria Toxin ◽  
Plaque Burden ◽  
Metabolic Dysfunction ◽  
Chronological Aging ◽  
Apoe Knockout Mice ◽  
Apoe Ko Mice ◽  
Novel Strategy ◽  
Underlying Mechanisms

Cellular senescence entails an irreversible growth arrest and a pro-inflammatory secretory phenotype, which contributes to aging-associated disorders such as atherosclerosis and diabetes, however, underlying mechanisms are largely unknown. In this study, we identified a novel protein, senescence-associated glycoprotein (SAGP), as a biomarker of cellular senescence and we also found that elimination of senescent cells targeting SAGP attenuated aging-associated disorders such as atherosclerosis and diabetes. First, we identified that SAGP as a senescent marker by microarray analysis of senescent human endothelial cells compared with young endothelial cells. The expression of SAGP was significantly increased in the aorta of chronological aging mice or ApoE-knockout mice. Then we measured SAGP expression in the patients registered in our hospital and found that mean SAGP expression was significantly higher in patients with atherosclerotic diseases compared to patients without atherosclerotic diseases.Recently, it is reported that elimination of senescent cells (senolysis) reversibly improved pathological aging phenotypes and also extended the lifespan. We established senolytic therapy targeting SAGP. We generated SAGP-DTR (diphtheria toxin receptor) transgenic mice, in which we could eliminate the SAGP- positive senescent cells using DT (diphtheria toxin). We found elimination of SAGP positive senescent cells significantly reduced the atherosclerotic plaque burden in the aorta of ApoE-KO mice and improved the glucose metabolism of dietary obese mice. For clinical implication, we then developed a cytotoxic vaccine targeting SAGP. Treatment with SAGP vaccine successfully eliminated SAGP positive senescent cells and attenuated atherosclerosis and metabolic dysfunction. These data indicate that targeting SAGP-positive cells could be a novel strategy for senolytic therapy.

Elimination of senescent cells targeting Senescence associated glycoprotein (SAGP) improved the ageing-associated diseases and extended the lifespan

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Suda ◽  
I Shimizu ◽  
G Katsuumi ◽  
Y Yoshida ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cellular Senescence ◽  
Diphtheria Toxin ◽  
Premature Aging ◽  
Plaque Burden ◽  
Funding Source ◽  
Metabolic Dysfunction ◽  
Human Endothelial Cells ◽  
Chronological Aging ◽  
National Budget

Abstract   Cellular senescence entails an irreversible growth arrest and a pro-inflammatory secretory phenotype, which contributes to aging-associated disorders such as atherosclerosis and diabetes, however, underlying mechanisms are largely unknown. In this study, we identified a novel protein, senescence-associated glycoprotein (SAGP), as a biomarker of cellular senescence and we also found that elimination of senescent cells targeting SAGP attenuated aging-associated disorders such as atherosclerosis, diabetes and frailty. First, we identified that SAGP as a senescent marker by microarray analysis of senescent human endothelial cells compared with young endothelial cells. The expression of SAGP was significantly increased in the aorta of chronological aging mice and ApoE-knockout mice. Then we measured SAGP expression in the patients registered in our hospital and found that mean SAGP expression was significantly higher in patients with atherosclerotic diseases compared to patients without atherosclerotic diseases. These data suggest that SAGP would become the novel marker of cellular senescence and/or aging-associated disorders. We found SAGP co-localized with lysosome and bound to V-ATPase, proton pump in the acid organelles such as lysosome. The electron microscopy analysis revealed that the dysfunctional lysosomes were accumulated in SAGP knockdown endothelial cell. The genetic deletion of SAGP resulted in the increase of lysosomal pH and the suppression of mitochondrial autophagy, mitophagy. And this associated with the high level of mitochondrial reactive oxygen species (ROS) and promoted premature senescence in human endothelial cells. These data suggest that SAGP was induced by the lysosomal stress in the senescent cells to protects senescent cells by maintaining the lysosomal homeostasis. Recently, it is reported that elimination of senescent cells (senolysis) reversibly improved pathological aging phenotypes and also extended the lifespan. We established senolytic therapy targeting SAGP. We generated SAGP-DTR (diphtheria toxin receptor) transgenic mice, in which we could eliminate the SAGP- positive senescent cells using DT (diphtheria toxin). We found elimination of SAGP positive senescent cells significantly reduced the atherosclerotic plaque burden in the aorta of ApoE-KO mice and improved the glucose metabolism of dietary obese mice, indicating that SAGP could be a useful target for senolytic therapy. For clinical implication, we then developed a cytotoxic vaccine targeting SAGP. Treatment with SAGP vaccine successfully eliminated SAGP positive senescent cells and attenuated atherosclerosis and metabolic dysfunction. Surprisingly, administration of SAGP vaccine to Zmpste24-KO mice, premature aging mice, extended the lifespan. These data indicate that targeting SAGP-positive cells could be a novel strategy for senolytic therapy. Effect of SAGP vaccine Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research by Japan Society for the Promotion of Science (JSPS)

5892Elimination of cells expressing Senescence associated glycoprotein (SAGP) attenuates the atherosclerotic diseases

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Suda ◽  
I Shimizu ◽  
Y Yoshida ◽  
G Katsuumi ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transgenic Mice ◽  
Atherosclerotic Plaque ◽  
Cellular Senescence ◽  
Knockout Mice ◽  
Diphtheria Toxin ◽  
Replicative Senescence ◽  
Plaque Burden ◽  
Human Endothelial Cells ◽  
Apoe Ko

Abstract Cellular senescence is defined as a state of irreversible growth arrest and is accompanied by changes of both cell morphology and gene expression. Although accumulation of senescent vascular endothelial cells impair the vessel homeostasis and promote atherosclerotic diseases, underlying mechanisms are largely unknown. In this study, we identified a novel protein, senescence-associated glycoprotein (SAGP), as a biomarker of cellular senescence and we found modulation of SAGP or elimination of senescent cells targeting SAGP would become a novel therapy for atherosclerotic diseases. We found that SAGP expression was significantly increased in human endothelial cells undergoing replicative senescence compared with young endothelial cells. We also found SAGP expression in aorta was significantly increased both in chronological aging mice or ApoE knockout mice. Furthermore, we measured SAGP expression in patients registered in our hospital and found that mean SAGP expression was significantly higher in patients with atherosclerotic diseases compared to patients without atherosclerotic diseases.These data suggest that SAGP would become a novel cellular senescence and/or atherosclerotic disease marker. Genetic deletion of SAGP resulted in high level of mitochondrial reactive oxygen species (ROS) and promoted premature senescence in human endothelial cells. And this associated with suppression of mitochondrial autophagy, mitophagy. We found SAGP co-localized with lysosome by immunocytochemistry. In addition, the electron microscopy analysis revealed that the dysfunctional lysosomes were accumulated in SAGP knockdown endothelial cell, suggesting that SAGP maintain lysosomal homeostasis. Next, wegenerated ApoE-KO/ SAGP overexpression mice and found that atherosclerotic plaque burden was attenuated in these double-transgenic mice. In contrast, SAGP/ApoE double knockout mice showed progression in atherosclerosis. These data suggest that modulation of SAGPwould become a new therapeutic target for atherosclerotic diseases. SAGP vaccine Recently, it is reported that elimination of senescent cells (senolysis) reversibly improved pathological aging phenotypes and also extended the lifespan. We have taken another approach for atherosclerotic diseases, senolytic therapy targeting SAGP. We generated SAGP-DTR (diphtheria toxin receptor) transgenic mice, in which we could eliminate the SAGP- positive senescent cells using DT (diphtheria toxin). We found elimination of SAGP positive senescent cells significantly reduced the atherosclerotic plaque burden, indicating that SAGP would become a useful target for senolytic therapy. We then developed a cytotoxic vaccine targeting SAGP. Treatment with SAGP vaccine successfully eliminated SAGP positive senescent cells. Administration of SAGP vaccine to ApoE-KO mice significantly reduced atherogenesis. These data indicate that targeting SAGP-positive cells could become a strategy for senolytic therapy.

scholarly journals Homocysteine Induces Apoptosis of Human Umbilical Vein Endothelial Cells via Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Zhimin Zhang ◽  
Congying Wei ◽  
Yanfen Zhou ◽  
Tao Yan ◽  
Zhengqiang Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Umbilical Vein ◽  
Dependent Manner ◽  
Human Umbilical Vein ◽  
Homologous Protein ◽  
Intracellular Ros ◽  
Underlying Mechanisms ◽  
Umbilical Vein Endothelial Cells

Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-κb. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy-induced HUVEC apoptosis and the activation of NF-κb. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-κb.

scholarly journals Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea

2015 ◽  
Vol 309 (7) ◽  
pp. H1101-H1111 ◽  
Author(s):  
Luciano F. Drager ◽  
Vsevolod Y. Polotsky ◽  
Christopher P. O'Donnell ◽  
Sergio L. Cravo ◽  
Geraldo Lorenzi-Filho ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Cardiovascular Risk ◽  
Sleep Apnea ◽  
Animal Models ◽  
Metabolic Dysfunction ◽  
Significant Progress ◽  
Glucose And Lipid Metabolism ◽  
Obstructive Sleep ◽  
Underlying Mechanisms ◽  
Made In

Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant pathophysiological disturbance in OSA–intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field.

Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells

2013 ◽  
Vol 90 (1) ◽  
pp. 71-80 ◽  
Author(s):  
Kwang Seok Kim ◽  
Jung Eun Kim ◽  
Kyu Jin Choi ◽  
Sangwoo Bae ◽  
Dong Ho Kim
Keyword(s):  
Dna Damage ◽  
Endothelial Cells ◽  
Ionizing Radiation ◽  
Cellular Senescence

scholarly journals Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

2021 ◽  
Vol 22 (21) ◽  
pp. 11629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Arturo Santos ◽  
Juan Armendariz-Borunda
Keyword(s):  
Insulin Resistance ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Causes Of Death ◽  
Cardiovascular Prevention ◽  
Atherogenic Dyslipidemia ◽  
Metabolic Dysfunction ◽  
Systemic Insulin Resistance ◽  
Underlying Mechanisms

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.

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.

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