scholarly journals The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Suowen Xu ◽  
Yujie Liu ◽  
Yu Ding ◽  
Sihui Luo ◽  
Xueying Zheng ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cardiovascular Complications ◽  
Monocyte Adhesion ◽  
Sequencing Data ◽  
Atorvastatin Treatment ◽  
Endothelial Inflammation ◽  
Tnf Α ◽  
Ameliorative Effect ◽  
Adhesive Molecules ◽  
Anti Inflammation

AbstractCoronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was 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 elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. 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). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.

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 Correlation Between Tumor Necrosis Factor-α Levels, Free Fatty Acid Levels, and Soluble Vascular Cell Adhesion Molecule-1 Levels in Rheumatoid Arthritis Patients

2018 ◽  
Vol 12 (1) ◽  
pp. 86-93 ◽  
Author(s):  
Fazria Nasriati ◽  
Rudy Hidayat ◽  
Budiman Budiman ◽  
Ikhwan Rinaldi
Keyword(s):  
Rheumatoid Arthritis ◽  
Endothelial Dysfunction ◽  
Negative Correlation ◽  
Acute Infection ◽  
Data Distribution ◽  
Cardiovascular Complications ◽  
Metabolic Disturbances ◽  
Cross Sectional ◽  
Tnf Α ◽  
Factor Α

Background:The mortality of Rheumatoid Arthritis (RA) is quite high, which is largely due to cardiovascular complications caused by endothelial dysfunction. One of the important inflammatory mediators that contribute to RA joints arthritis of TNF-α, also proven to play a role in endothelial dysfunction and play a role in increasing intracellular lipolysis, thus increasing circulating FFA levels.Objectives:To determine the correlation between TNF-α levels with VCAM-1 levels, correlation of TNF-α levels with FFA levels, and correlation of FFA levels with VCAM-1 levels.Methods:Cross sectional and retrospective design studies of adult RA patients treated at Cipto Mangunkusumo Hospital (RSCM), without metabolic disturbances, acute infection, cardiovascular disorders, or other autoimmune diseases. The cross-sectional data was collected from October to November 2017, while retrospective samples were collected since August 2016. TNF-α, VCAM-1, and FFA levels were assessed by serum blood test by ELISA method. Correlation analysis is done by Pearson analysis when the data distribution is normal and with Spearman analysis when the data distribution is not normal.Results:A total of 35 subjects were enrolled in the study. Most (97.1%) were women with an average age of 45.29 years, median disease duration of 48 months, and most had moderate disease activity (65.7%). No significant correlation was found between TNF-α levels and VCAM-1 levels (p = 0.677; r = +0.073). as well betwen TNF-α levels and FFA levels (p = 0.227; r = -0.21). The correlation between FFA and VCAM-1 levels showed significant correlation with negative correlation and weak correlation (p = 0.036; r = -0.355).Conclusions:(1) There was no correlation between TNF-α levels and VCAM-1 levels in RA patients; (2) There was no correlation between TNF-α levels and FFA levels in RA patients; (3) There was a negative correlation between FFA levels and VCAM-1 levels in RA patients.

scholarly journals Differential Effects of Ruminant and Industrial 18-Carbon trans-Monounsaturated Fatty Acids (trans Vaccenic and Elaidic) on the Inflammatory Responses of an Endothelial Cell Line

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5834
Author(s):  
Carina A. Valenzuela ◽  
Ella J. Baker ◽  
Camila O. De Souza ◽  
Elizabeth A. Miles ◽  
Philip C. Calder
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Endothelial Dysfunction ◽  
Inflammatory Responses ◽  
Vaccenic Acid ◽  
Dependent Manner ◽  
Monocyte Adhesion ◽  
Necrosis Factor Alpha ◽  
Differential Effects ◽  
Tnf Α

Endothelial dysfunction and inflammation are recognised factors in the development of atherosclerosis. Evidence suggests that intake of industrial trans fatty acids (TFAs) promotes endothelial dysfunction, while ruminant TFAs may have the opposite effect. The aim of this study was to compare the effects of elaidic acid (EA (18:1n-9t); an industrially produced TFA) and trans vaccenic acid (TVA (18:1n-7t); a natural TFA found in ruminant milk and meat) on inflammatory responses of endothelial cells (ECs). ECs (EA.hy926 cells) were cultured under standard conditions and exposed to TFAs (1 to 50 μM) for 48 h. Then, the cells were cultured for a further 6 or 24 h with tumour necrosis factor alpha (TNF-α, 1 ng/mL) as an inflammatory stimulant. ECs remained viable after treatments. TFAs were incorporated into ECs in a dose-dependent manner. Preincubation with EA (50 µM) increased production of MCP-1, RANTES, and IL-8 in response to TNF-α, while preincubation with TVA (1 µM) decreased production of ICAM-1 and RANTES in response to TNF-α. Preincubation with EA (50 µM) upregulated toll-like receptor 4 and cyclooxygenase 2 gene expression in response to TNF-α. In contrast, preincubation with TVA (1 µM) downregulated TNF-α induced nuclear factor kappa B subunit 1 gene expression. Preincubation of ECs with EA (50 µM) increased THP-1 monocyte adhesion. In contrast, preincubation of ECs with TVA (1 µM) reduced THP-1 monocyte adhesion, while preincubation of ECs with TVA (50 µM) decreased the level of surface expression of ICAM-1 seen following TNF-α stimulation. The results suggest that TVA has some anti-inflammatory properties, while EA enhances the response to an inflammatory stimulus. These findings suggest differential effects induced by the TFAs tested, fitting with the idea that industrial TFAs and ruminant TFAs can have different and perhaps opposing biological actions in an inflammatory context.

scholarly journals Endothelial Dysfunction in Obesity-Induced Inflammation: Molecular Mechanisms and Clinical Implications

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 291 ◽  
Author(s):  
Ibrahim Kalle Kwaifa ◽  
Hasnah Bahari ◽  
Yoke Keong Yong ◽  
Sabariah Md Noor
Keyword(s):  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Cardiovascular Complications ◽  
The Body ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Tnf Α ◽  
Factor Α ◽  
And Control ◽  
Stimulation Of

Obesity is characterized by the excessive deposition of fat that may interfere with the normal metabolic process of the body. It is a chronic condition associated with various metabolic syndromes, whose prevalence is grossly increasing, and affects both children and adults. Accumulation of excessive macronutrients on the adipose tissues promotes the secretion and release of inflammatory mediators, including interleukin-6 (IL-6), interleukin 1β, tumor necrotic factor-α (TNF-α), leptin, and stimulation of monocyte chemoattractant protein-1 (MCP-1), which subsequently reduce the production of adiponectin thereby initiating a proinflammatory state. During obesity, adipose tissue synthesizes and releases a large number of hormones and cytokines that alter the metabolic processes, with a profound influence on endothelial dysfunction, a situation associated with the formation of atherosclerotic plaque. Endothelial cells respond to inflammation and stimulation of MCP-1, which is described as the activation of adhesion molecules leading to proliferation and transmigration of leukocytes, which facilitates their increase in atherogenic and thromboembolic potentials. Endothelial dysfunction forms the cornerstone of this discussion, as it has been considered as the initiator in the progression of cardiovascular diseases in obesity. Overexpression of proinflammatory cytokines with subsequent reduction of anti-inflammatory markers in obesity, is considered to be the link between obesity-induced inflammation and endothelial dysfunction. Inhibition of inflammatory mechanisms and management and control of obesity can assist in reducing the risks associated with cardiovascular complications.

scholarly journals Evaluation of Endothelial Dysfunction and Autophagy in Fibromyalgia-Related Vascular and Cerebral Cortical Changes and the Ameliorative Effect of Fisetin

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 48
Author(s):  
Fatma Mohamed Ghoneim ◽  
Salwa Mohamed Abo-Elkhair ◽  
Ayman Zaky Elsamanoudy ◽  
Dalia A. Shabaan
Keyword(s):  
Endothelial Dysfunction ◽  
Carotid Arteries ◽  
Caspase 3 ◽  
Rna Extraction ◽  
Pain Syndrome ◽  
Treated Group ◽  
Albino Rats ◽  
Tissue Samples ◽  
Tnf Α ◽  
Ameliorative Effect

Fibromyalgia (FM) is a common chronic pain syndrome that affects 1% to 5% of the population. We aimed to investigate the role of endothelial dysfunction and autophagy in fibromyalgia-related vascular and cerebral cortical changes in a reserpine-induced rat model of fibromyalgia at the histological and molecular levels and to study the ameliorative effect of fisetin. Forty adult female albino rats were divided into four groups (10 each): two control groups, the reserpine-induced fibromyalgia group, and the fisetin-treated group. The carotid arteries and brains of the animals were dissected. Frozen tissue samples were used for total RNA extraction and qPCR analysis of eNOS, caspase-3, Bcl-2, LC-3, BECN-1, CHOP, and TNF-α expression. Histological, immunohistochemical (eNOS), and ultrastructure studies were conducted. The carotid arteries revealed excessive autophagy and endothelial, vascular, and apoptotic changes. The cerebral cortex showed similar findings apart from endoplasmic reticulum stress. Additionally, there was decreased gene expression of eNOS and Bcl-2 and increased expression of caspase-3, LC-3, BECN-1, CHOP, and TNF-α. In the fisetin-treated rats, improvements in the histological and molecular results were detected. In conclusion, oxidative stress, enhanced apoptosis, and excessive autophagy are fundamental pathophysiologic mechanisms of reserpine-induced fibromyalgia. Moreover, fisetin has an ameliorative effect against fibromyalgia.

scholarly journals Free radicals and endothelial dysfunction: Potential positive effects of TNF-α inhibitors

Redox Report ◽  
2013 ◽  
Vol 18 (3) ◽  
pp. 95-99 ◽  
Author(s):  
Giuseppe Murdaca ◽  
Francesca Spanò ◽  
Paola Cagnati ◽  
Francesco Puppo
Keyword(s):  
Free Radicals ◽  
Endothelial Dysfunction ◽  
Positive Effects ◽  
Tnf Α

scholarly journals BAM15, a Mitochondrial Uncoupling Agent, Attenuates Inflammation in the LPS Injection Mouse Model: An Adjunctive Anti-Inflammation on Macrophages and Hepatocytes

2021 ◽  
pp. 1-17
Author(s):  
Cong Phi Dang ◽  
Jiraphorn Issara-Amphorn ◽  
Awirut Charoensappakit ◽  
Kanyarat Udompornpitak ◽  
Thansita Bhunyakarnjanarat ◽  
...  
Keyword(s):  
Atp Depletion ◽  
Organ Injury ◽  
Flux Analysis ◽  
Energy Status ◽  
Mitochondrial Uncoupling ◽  
Inflammatory Monocytes ◽  
Tnf Α ◽  
Cell Energy ◽  
Anti Inflammatory ◽  
Anti Inflammation

Controlof immune responses through the immunometabolism interference is interesting for sepsis treatment. Then, expression of immunometabolism-associated genes and BAM15, a mitochondrial uncoupling agent, was explored in a proinflammatory model using lipopolysaccharide (LPS) injection. Accordingly, the decreased expression of mitochondrial uncoupling proteins was demonstrated by transcriptomic analysis on metabolism-associated genes in macrophages (RAW246.7) and by polymerase chain reaction in LPS-stimulated RAW246.7 and hepatocytes (Hepa 1–6). Pretreatment with BAM15 at 24 h prior to LPS in macrophages attenuated supernatant inflammatory cytokines (IL-6, TNF-α, and IL-10), downregulated genes of proinflammatory M1 polarization (iNOS and IL-1β), upregulated anti-inflammatory M2 polarization (Arg1 and FIZZ), and decreased cell energy status (extracellular flux analysis and ATP production). Likewise, BAM15 decreased expression of proinflammatory genes (IL-6, TNF-α, IL-10, and iNOS) and reduced cell energy in hepatocytes. In LPS-administered mice, BAM15 attenuated serum cytokines, organ injury (liver enzymes and serum creatinine), and tissue cytokines (livers and kidneys), in part, through the enhanced phosphorylated αAMPK, a sensor of ATP depletion with anti-inflammatory property, in the liver, and reduced inflammatory monocytes/macrophages (Ly6C +ve, CD11b +ve) in the liver as detected by Western blot and flow cytometry, respectively. In conclusion, a proof of concept for inflammation attenuation of BAM15 through metabolic interference-induced anti-inflammation on macrophages and hepatocytes was demonstrated as a new strategy of anti-inflammation in sepsis.

scholarly journals Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Basma Basha ◽  
Samson Mathews Samuel ◽  
Chris R. Triggle ◽  
Hong Ding
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Clinical Trials ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Therapeutic Agents ◽  
Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

scholarly journals Suicidal Erythrocyte Death in Metabolic Syndrome

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 154
Author(s):  
Ignazio Restivo ◽  
Alessandro Attanzio ◽  
Luisa Tesoriere ◽  
Mario Allegra
Keyword(s):  
Metabolic Syndrome ◽  
Cell Death ◽  
Endothelial Dysfunction ◽  
Cell Membrane ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Inflammatory Milieu ◽  
Cardiometabolic Factors

Eryptosis is a coordinated, programmed cell death culminating with the disposal of cells without disruption of the cell membrane and the release of endocellular oxidative and pro-inflammatory milieu. While providing a convenient form of death for erythrocytes, dysregulated eryptosis may result in a series of detrimental and harmful pathological consequences highly related to the endothelial dysfunction (ED). Metabolic syndrome (MetS) is described as a cluster of cardiometabolic factors (hyperglycemia, dyslipidemia, hypertension and obesity) that increases the risk of cardiovascular complications such as those related to diabetes and atherosclerosis. In the light of the crucial role exerted by the eryptotic process in the ED, the focus of the present review is to report and discuss the involvement of eryptosis within MetS, where vascular complications are utterly relevant. Current knowledge on the mechanisms leading to eryptosis in MetS-related conditions (hyperglycemia, dyslipidemia, hypertension and obesity) will be analyzed. Moreover, clinical evidence supporting or proposing a role for eryptosis in the ED, associated to MetS cardiovascular complications, will be discussed.

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