Evidence map›Paper›PMID 27006445›Full record

ArticleCirculation research2016

Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells.

Hang Xi, Yuling Zhang, Yanjie Xu, William Y Yang, Xiaohua Jiang, Xiaojin Sha, Xiaoshu Cheng, Jingfeng Wang, Xuebin Qin, Jun Yu and 3 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 160 papers.

0numbers the graph read from it
0cells of the map it votes in
160citing papers in PubMed
11.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

160 citing papers in PubMed, 225 citations in OpenAlex.

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100 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 1 country.

Hang XiFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Yuling ZhangFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Yanjie XuFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
William Y YangFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Xiaohua JiangFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Xiaojin ShaFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Xiaoshu ChengFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Jingfeng WangFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Xuebin QinFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Jun YuFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Yong JiFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.). hongw@temple.edu.
Xiaofeng YangFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.).
Hong WangFrom the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of Cardiovascular Disease in Nanchang University, Nan Chang, Jiang Xi, China (Y.X., X.C.); and Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China (Y.J.). hongw@temple.edu.
Nanchang University · CNSecond Affiliated Hospital of Nanchang University · CNSecond Hospital of Nanchang · CN

Funding

WORD PROCESSING CENTER--COREP30CA006927 · NCI · RESEARCH INST OF FOX CHASE CAN CTR · PI Margaret von Mehren · 1985 to 2026
$138.8M
Atherogenic mechanisms with homocysteineR01HL077288 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI WANG, HONG · 2004 to 2014
$3.8M
Inhibition of Endothelial Growth by HomocysteineR01HL067033 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI WANG, HONG · 2002 to 2011
$3.0M
Hyperhomocysteinemia and HDL MetabolismR01HL117654 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI WANG, HONG · 2013 to 2017
$3.0M
Caspase-1 activation mediates chronic kidney disease-accelerated atherosclerosisR01HL131460 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI CHOI, ERIC T., WANG, HONG · 2016 to 2019
$2.8M
NADHP Oxidase-mediated MC differentiation & Endothelial Dysfunction in HHcyR01HL110764 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI WANG, HONG · 2011 to 2015
$2.5M
Atherogenic roles of complement systemR01HL130233 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI QIN, XUEBIN, WANG, HONG · 2016 to 2019
$2.5M
IL-35 suppression of endothelial cell activation and atherosclerosisR01HL132399 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI YANG, XIAOFENG · 2017 to 2020
$2.3M
HHcy-induced Inflammatory Monocyte and Macrophage Differentiation in DiabetesR01DK104116 · NIDDK · TEMPLE UNIV OF THE COMMONWEALTH · PI WANG, HONG · 2015 to 2019
$2.2M
Roles of Interleukin-17 in Endothelial CellsR01HL108910 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI YANG, XIAOFENG · 2011 to 2015
$1.9M
Suppression of vascular endothelial cell inflammationR01HL094451 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI YANG, XIAOFENG · 2009 to 2013
$1.8M
Role of HHcy in diabetic vascular diseaseR01HL082774 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI WANG, HONG · 2006 to 2010
$1.8M
NCI NIH HHS P30 CA006927NHLBI NIH HHS F32 HL009445NHLBI NIH HHS R01 HL067033NHLBI NIH HHS R01 HL077288NHLBI NIH HHS R01 HL082774NHLBI NIH HHS R01 HL094451NHLBI NIH HHS R01 HL108910NHLBI NIH HHS R01 HL110764NHLBI NIH HHS R01 HL116917NHLBI NIH HHS R01 HL117654NHLBI NIH HHS R01 HL130233NHLBI NIH HHS R01 HL131460NHLBI NIH HHS R01 HL132399NIDDK NIH HHS R01 DK104116
6 · The paper itself

Abstract

rationaleEndothelial injury is an initial mechanism mediating cardiovascular disease.

objectiveHere, we investigated the effect of hyperhomocysteinemia on programed cell death in endothelial cells (EC). METHODS AND

resultsWe established a novel flow-cytometric gating method to define pyrotosis (Annexin V(-)/Propidium iodide(+)). In cultured human EC, we found that: (1) homocysteine and lipopolysaccharide individually and synergistically induced inflammatory pyroptotic and noninflammatory apoptotic cell death; (2) homocysteine/lipopolysaccharide induced caspase-1 activation before caspase-8, caspase-9, and caspase-3 activations; (3) caspase-1/caspase-3 inhibitors rescued homocysteine/lipopolysaccharide-induced pyroptosis/apoptosis, but caspase-8/caspase-9 inhibitors had differential rescue effect; (4) homocysteine/lipopolysaccharide-induced nucleotide-binding oligomerization domain, and leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) protein caused NLRP3-containing inflammasome assembly, caspase-1 activation, and interleukin (IL)-1β cleavage/activation; (5) homocysteine/lipopolysaccharide elevated intracellular reactive oxygen species, (6) intracellular oxidative gradient determined cell death destiny as intermediate intracellular reactive oxygen species levels are associated with pyroptosis, whereas high reactive oxygen species corresponded to apoptosis; (7) homocysteine/lipopolysaccharide induced mitochondrial membrane potential collapse and cytochrome-c release, and increased B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 ratio which were attenuated by antioxidants and caspase-1 inhibitor; and (8) antioxidants extracellular superoxide dismutase and catalase prevented homocysteine/lipopolysaccharide -induced caspase-1 activation, mitochondrial dysfunction, and pyroptosis/apoptosis. In cystathionine β-synthase-deficient (Cbs(-/-)) mice, severe hyperhomocysteinemia-induced caspase-1 activation in isolated lung EC and caspase-1 expression in aortic endothelium, and elevated aortic caspase-1, caspase-9 protein/activity and B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 ratio in Cbs(-/-) aorta and human umbilical vein endothelial cells. Finally, homocysteine-induced DNA fragmentation was reversed in caspase-1(-/-) EC. Hyperhomocysteinemia-induced aortic endothelial dysfunction was rescued in caspase-1(-/-) and NLRP3(-/-) mice.

conclusionsHyperhomocysteinemia preferentially induces EC pyroptosis via caspase-1-dependent inflammasome activation leading to endothelial dysfunction. We termed caspase-1 responsive pyroptosis and apoptosis as pyrop-apoptosis.

Indexed as

PyroptosisAnimalsbcl-2-Associated X ProteinCaspase 1Cystathionine beta-SynthaseHomocysteineHumansHuman Umbilical Vein Endothelial CellsInflammasomesInterleukin-1betaLipopolysaccharidesMiceMice, Inbred C57BLNLR Family, Pyrin Domain-Containing 3 ProteinReactive Oxygen Speciesbcl-2-Associated X ProteinCaspase 1Cystathionine beta-SynthaseHomocysteineInflammasomesInterleukin-1betaLipopolysaccharidesNLR Family, Pyrin Domain-Containing 3 ProteinNlrp3 protein, mouseReactive Oxygen Speciesapoptosiscaspase-1endothelial cellshomocysteinepyroptosis

Identifiers

PMID27006445
PMCPMC4867131
OpenAlexW2304527713

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.