The Shear Stress/KLF2/Nrf2/ARE Pathway: A Hemodynamic Defense against Oxidative Stress

Many diseases have oxidative stress and inflammation as underlying pathological features, including metabolic and inflammatory/autoimmune disorders, diseases of the lung, liver, kidney, gastrointestinal tract, cardiovascular and nervous systems. A leading physiological mechanism for oxidative stress is the nuclear erythroid-related factor 2-like 2/antioxidant response element (Nrf2/ARE) signaling pathway. It maintains intracellular homeostasis and protects cells from oxidative damage by inducing phase II detoxifying and oxidative-stress responsive genes. Nrf2 transcription factor functions as the key controller of the redox homeostatic gene regulatory network, and is tightly controlled by the repressor protein, Kelch-like ECH-associated protein 1 (Keap1). Pharmacological agents to inhibit Keap1 and boost effectiveness of the Nrf2/ARE pathway have been developed and more are in development. This chapter elucidates the importance of hemodynamic laminar shear stress in oxidative homeostasis and examines hemodynamic induction of the shear stress (SS)/Krupple-like factor2 (KLF2) /Nrf2/ARE pathway as a means to combat oxidative stress through hemodynamics.

Laminar shear stress inhibits lipid peroxidation induced by high glucose plus arachidonic acid in endothelial cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00727.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. H1966-H1973 ◽

Cited By ~ 16

Author(s):

Gyeong In Mun ◽

Sang Mi An ◽

Heonyong Park ◽

Hanjoong Jo ◽

Yong Chool Boo

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Endothelial Cells ◽

Shear Stress ◽

Arachidonic Acid ◽

High Glucose ◽

Critical Role ◽

Antioxidant Effect ◽

Laminar Shear Stress ◽

Elevated blood glucose and free fatty acids induce oxidative stress associated with the incidence of cardiovascular disease. In contrast, laminar shear stress (LSS) plays a critical role in maintaining vascular health. The present study examined the mechanism for the antioxidant effect of LSS attenuating the oxidative stress induced by high glucose (HG) and arachidonic acid (AA) in human umbilical vein endothelial cells. HG and AA synergistically decreased cell viability and increased glutathione (GSH) oxidation and lipid peroxidation. The lipid peroxidation was markedly prevented by LSS as well as tetrahydrobiopterin (BH4) and GSH. LSS increased BH4 and GSH contents, and expression of GTP cyclohydrolase-1 and glutamylcysteine ligase (GCL) involved in their biosynthesis. Inhibition of GCL activity by DL-buthionine-(S,R)-sulfoximine and small-interfering RNA-mediated knockdown of GCL lessened the antioxidant effect of LSS. Therefore, it is suggested that LSS enhances antioxidant capacity of endothelial cells and thereby attenuates the oxidative stress caused by cardiovascular risk factors.

Neuroprotection of chromobox 7 knockout in the mouse after cerebral ischemia-reperfusion injury via nuclear factor E2-related factor 2/hemeoxygenase-1 signaling pathway

Human & Experimental Toxicology ◽

10.1177/09603271211036122 ◽

2021 ◽

pp. 096032712110361

Author(s):

Hai-Tao Zhang ◽

Xi-Zeng Wang ◽

Qing-Mei Zhang ◽

Han Zhao

Keyword(s):

Oxidative Stress ◽

Cerebral Ischemia ◽

Infarct Size ◽

Water Content ◽

Cell Apoptosis ◽

Ischemia Reperfusion ◽

Related Factor ◽

Nuclear Factor ◽

Cerebral Ischemia Reperfusion ◽

Objective To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. Methods The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress–related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. Results At 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. Conclusion Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.

Epigenetic histones modification and cardiovascular lineage programming in mouse embryonic stem cells exposed to laminar shear stress

Vascular Pharmacology ◽

10.1016/j.vph.2006.08.148 ◽

2006 ◽

Vol 45 (3) ◽

pp. e56

Author(s):

Barbara Illi ◽

Alessandro Scopece ◽

Simona Nanni ◽

Antonella Farsetti ◽

Liliana Morgante ◽

...

Keyword(s):

Stem Cells ◽

Shear Stress ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cells ◽

Laminar Shear Stress ◽

Laminar shear stress upregulates endothelial Ca2+-activated K+ channels KCa2.3 and KCa3.1 via a Ca2+/calmodulin-dependent protein kinase kinase/Akt/p300 cascade

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00642.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. H484-H493 ◽

Cited By ~ 18

Author(s):

Jun Takai ◽

Alexandra Santu ◽

Haifeng Zheng ◽

Sang Don Koh ◽

Masanori Ohta ◽

...

Keyword(s):

Shear Stress ◽

Transcriptional Activation ◽

Static Condition ◽

Fold Increase ◽

Laminar Shear Stress ◽

Human Coronary Artery ◽

Intracellular Ca ◽

Kinase Cascade ◽

Dependent Protein ◽

In endothelial cells (ECs), Ca2+-activated K+ channels KCa2.3 and KCa3.1 play a crucial role in the regulation of arterial tone via producing NO and endothelium-derived hyperpolarizing factors. Since a rise in intracellular Ca2+ levels and activation of p300 histone acetyltransferase are early EC responses to laminar shear stress (LS) for the transcriptional activation of genes, we examined the role of Ca2+/calmodulin-dependent kinase kinase (CaMKK), the most upstream element of a Ca2+/calmodulin-kinase cascade, and p300 in LS-dependent regulation of KCa2.3 and KCa3.1 in ECs. Exposure to LS (15 dyn/cm2) for 24 h markedly increased KCa2.3 and KCa3.1 mRNA expression in cultured human coronary artery ECs (3.2 ± 0.4 and 45 ± 10 fold increase, respectively; P < 0.05 vs. static condition; n = 8–30), whereas oscillatory shear (OS; ± 5 dyn/cm2 × 1 Hz) moderately increased KCa3.1 but did not affect KCa2.3. Expression of KCa2.1 and KCa2.2 was suppressed under both LS and OS conditions, whereas KCa1.1 was slightly elevated in LS and unchanged in OS. Inhibition of CaMKK attenuated LS-induced increases in the expression and channel activity of KCa2.3 and KCa3.1, and in phosphorylation of Akt (Ser473) and p300 (Ser1834). Inhibition of Akt abolished the upregulation of these channels by diminishing p300 phosphorylation. Consistently, disruption of the interaction of p300 with transcription factors eliminated the induction of these channels. Thus a CaMKK/Akt/p300 cascade plays an important role in LS-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes.

Antioxidant Therapy in Pancreatitis

Antioxidants ◽

10.3390/antiox10050657 ◽

2021 ◽

Vol 10 (5) ◽

pp. 657

Author(s):

Lourdes Swentek ◽

Dean Chung ◽

Hirohito Ichii

Keyword(s):

Oxidative Stress ◽

Chronic Pancreatitis ◽

Total Pancreatectomy ◽

Current Status ◽

Related Factor ◽

Endocrine Dysfunction ◽

Deep Dive ◽

Pathway Activation ◽

Advanced Therapies ◽

Pancreatitis is pathologic inflammation of the pancreas characterized by acinar cell destruction and oxidative stress. Repeated pancreatic insults can result in the development of chronic pancreatitis, characterized by irreversible fibrosis of the pancreas and many secondary sequelae, ultimately leading to the loss of this important organ. We review acute pancreatitis, chronic pancreatitis, and pancreatitis-related complications. We take a close look at the pathophysiology with a focus on oxidative stress and how it contributes to the complications of the disease. We also take a deep dive into the evolution and current status of advanced therapies for management including dietary modification, antioxidant supplementation, and nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1(Nrf2-keap1) pathway activation. In addition, we discuss the surgeries aimed at managing pain and preventing further endocrine dysfunction, such as total pancreatectomy with islet auto-transplantation.

Reduction of doxorubicin-induced cytotoxicity and mitochondrial damage by betanin in rat isolated cardiomyocytes and mitochondria

Human & Experimental Toxicology ◽

10.1177/09603271211022800 ◽

2021 ◽

pp. 096032712110228

Author(s):

AA Hafez ◽

Z Jamali ◽

S Samiei ◽

S Khezri ◽

A Salimi

Keyword(s):

Oxidative Stress ◽

Protective Effect ◽

Bioactive Compound ◽

Isolated Cardiomyocytes ◽

Cardiac Inflammation ◽

Flow Cytometric ◽

Significant Toxicity ◽

Ros Formation ◽

Gene Regulatory ◽

Doxorubicin (DOX) is an anticancer drug which is used for treatment of several types of cancers. But the clinical use of doxorubicin is limited because of its cardiotoxicity and cardiomyopathy. Mitochondrial-dependent oxidative stress and cardiac inflammation appear to be involved in doxorubicin-induced cardiotoxicity. Betanin as a bioactive compound in Beetroot ( Beta vulgaris L.) displays anti-radical, antioxidant gene regulatory and cardioprotective activities. In this current study, we investigated the protective effect of betanin on doxorubicin-induced cytotoxicity and mitochondrial-dependent oxidative stress in isolated cardiomyocytes and mitochondria. Isolated cardiomyocytes and mitochondria were treated with three concentrations of betanin (1, 5 and 10 µM) and doxorubicin (3.5 µM) for 6 h. The parameters of cellular and mitochondrial toxicity were analyzed using biochemical and flow cytometric methods. Our results showed a significant toxicity in isolated cardiomyocytes and mitochondria in presence of doxorubicin which was related to reactive oxygen species (ROS) formation, increase in malondialdehyde (MDA), increase in oxidation of GSH to GSSG, lysosomal/mitochondrial damages and mitochondrial swelling. While betanin pretreatment reverted doxorubicin-induced cytotoxicity and oxidative stress in isolated cardiomyocytes and mitochondria. These results suggest that betanin elicited a typical protective effect on doxorubicin-induced cytotoxicity and oxidative stress. It is possible that betanin could be used as a useful adjuvant in combination with doxorubicin chemotherapy for reduction of cardiotoxicity and cardiomyopathy.

Daphnetin Ameliorates Corticosterone-Induced Depressive-Like Behavior and Oxidative Stress in Mice Via Nuclear Factor Erythroid 2-Related Factor/Heme Oxygenase-1 Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:470-476 ◽

2021 ◽

Vol 19 (4) ◽

pp. 470-476

Author(s):

Chao Liu ◽

Chao Liang ◽

Jie Huang

Keyword(s):

Oxidative Stress ◽

Consumption Rate ◽

Tail Suspension Test ◽

Protein Carbonyl ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Sucrose Consumption ◽

Markers Of Oxidative Stress ◽

Swimming Test ◽

We have investigated the effect of daphnetin on depressive-like behavior and oxidative stress caused by corticosterone in mice. To this end, we have analyzed the effect of corticosterone alone and combination of corticosterone and daphnetin on three behavioral indices of depressive-like behavior - sucrose consumption rate, forced swimming test, and tail suspension test as well as biochemical markers of oxidative stress - malondialdehyde, nitrite, protein carbonyl, nonprotein sulfhydryl and glutathione contents as well as hippocampal cell apoptosis. The results support the conclusion that daphnetin diminished corticosterone induced depressive like behavior and oxidative stress by activating Nrf2/HO-1 pathway.

Laminar Shear Stress Inhibits Endothelial Cell Metabolism via KLF2-Mediated Repression of PFKFB3

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.114.304277 ◽

2015 ◽

Vol 35 (1) ◽

pp. 137-145 ◽

Cited By ~ 117

Author(s):

Anuradha Doddaballapur ◽

Katharina M. Michalik ◽

Yosif Manavski ◽

Tina Lucas ◽

Riekelt H. Houtkooper ◽

...

Keyword(s):

Shear Stress ◽

Endothelial Cell ◽

Cell Metabolism ◽

Laminar Shear Stress ◽

Laminar Shear ◽

Endothelial Cell Metabolism

Endothelial albumin permeability is shear dependent, time dependent, and reversible

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.260.6.h1992 ◽

1991 ◽

Vol 260 (6) ◽

pp. H1992-H1996 ◽

Cited By ~ 32

Author(s):

H. Jo ◽

R. O. Dull ◽

T. M. Hollis ◽

J. M. Tarbell

Keyword(s):

Shear Stress ◽

Endothelial Cell ◽

Fluorescein Isothiocyanate ◽

Vascular Wall ◽

Laminar Shear Stress ◽

Aortic Endothelial Cells ◽

Transendothelial Permeability ◽

Steady Laminar Shear Stress ◽

Altered permeability of vascular endothelium to macromolecules may play a role in vascular disease as well as vascular homeostasis. Because the shear stress of flowing blood on the vascular wall is known to influence many endothelial cell properties, an in vitro system to measure transendothelial permeability (Pe) to fluorescein isothiocyanate conjugated bovine serum albumin under defined physiological levels of steady laminar shear stress was developed. Bovine aortic endothelial cells grown on polycarbonate filters pretreated with gelatin and fibronectin constituted the model system. Onset of 1 dyn/cm2 shear stress resulted in a Pe rise from 5.1 +/- 1.3 x 10(-6) cm/s to 21.9 +/- 4.6 X 10(-6) cm/s at 60 min (n = 6); while 10 dyn/cm2 shear stress increased Pe from 4.8 +/- 1.5 X 10(-6) cm/s to 50.2 +/- 6.8 X 10(-6) cm/s at 30 min and 49.6 +/- 8.9 X 10(-6) cm/s at 60 (n = 9). Pe returned to preshear values within 120 and 60 min after removal of 1 and 10 dyn/cm2 shear stress, respectively. The data show that endothelial cell Pe in vitro is acutely sensitive to shear stress.

SENCR stabilizes vascular endothelial cell adherens junctions through interaction with CKAP4

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810729116 ◽

2018 ◽

Vol 116 (2) ◽

pp. 546-555 ◽

Cited By ~ 28

Author(s):

Qing Lyu ◽

Suowen Xu ◽

Yuyan Lyu ◽

Mihyun Choi ◽

Christine K. Christie ◽

...

Keyword(s):

Shear Stress ◽

Endothelial Cell ◽

Noncoding Rna ◽

Rna Binding ◽

Adherens Junctions ◽

Vascular Endothelial Cell ◽

Membrane Integrity ◽

Laminar Shear Stress ◽

Loss Of Function ◽

SENCR is a human-specific, vascular cell-enriched long-noncoding RNA (lncRNA) that regulates vascular smooth muscle cell and endothelial cell (EC) phenotypes. The underlying mechanisms of action of SENCR in these and other cell types is unknown. Here, levels of SENCR RNA are shown to be elevated in several differentiated human EC lineages subjected to laminar shear stress. Increases in SENCR RNA are also observed in the laminar shear stress region of the adult aorta of humanized SENCR-expressing mice, but not in disturbed shear stress regions. SENCR loss-of-function studies disclose perturbations in EC membrane integrity resulting in increased EC permeability. Biotinylated RNA pull-down and mass spectrometry establish an abundant SENCR-binding protein, cytoskeletal-associated protein 4 (CKAP4); this ribonucleoprotein complex was further confirmed in an RNA immunoprecipitation experiment using an antibody to CKAP4. Structure–function studies demonstrate a noncanonical RNA-binding domain in CKAP4 that binds SENCR. Upon SENCR knockdown, increasing levels of CKAP4 protein are detected in the EC surface fraction. Furthermore, an interaction between CKAP4 and CDH5 is enhanced in SENCR-depleted EC. This heightened association appears to destabilize the CDH5/CTNND1 complex and augment CDH5 internalization, resulting in impaired adherens junctions. These findings support SENCR as a flow-responsive lncRNA that promotes EC adherens junction integrity through physical association with CKAP4, thereby stabilizing cell membrane-bound CDH5.