scholarly journals MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases

2017 ◽  
Vol 114 (8) ◽  
pp. 2072-2077 ◽  
Author(s):  
Ding-Yu Lee ◽  
Ting-Er Lin ◽  
Chih-I Lee ◽  
Jing Zhou ◽  
Yi-Hsuan Huang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Histone Deacetylases ◽  
Inflammatory Responses ◽  
Nuclear Accumulation ◽  
Hemodynamic Forces ◽  
Endothelial Response ◽  
Vascular Physiology ◽  
Responsive Element ◽  
Retinoid Acid

Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic factors in the regulation of vascular physiology. This study aimed to elucidate the relationship between HDACs and miRs in the hemodynamic modulation of endothelial cell (EC) dysfunction. We found that miR-10a has the lowest expression among all examined shear-responsive miRs in ECs under oscillatory shear stress (OS), and a relatively high expression under pulsatile shear stress (PS). PS and OS alter EC miR-10a expression to regulate the expression of its direct target GATA6 and downstream vascular cell adhesion molecule (VCAM)-1. PS induces the expression, nuclear accumulation, and association of retinoid acid receptor-α (RARα) and retinoid X receptor-α (RXRα). RARα and RXRα serve as a “director” and an “enhancer,” respectively, to enhance RARα binding to RA-responsive element (RARE) and hence miR-10a expression, thus down-regulating GATA6/VCAM-1 signaling in ECs. In contrast, OS induces associations of “repressors” HDAC-3/5/7 with RARα to inhibit the RARα-directed miR-10a signaling. The flow-mediated miR-10a expression is regulated by Krüppel-like factor 2 through modulation in RARα–RARE binding, with the consequent regulation in GATA6/VCAM-1 in ECs. These results are confirmed in vivo by en face staining on the aortic arch vs. the straight thoracic aorta of rats. Our findings identify a mechanism by which HDACs and RXRα modulate the hormone receptor RARα to switch miR-10a expression and hence the proinflammatory vs. anti-inflammatory responses of vascular endothelium under different hemodynamic forces.

scholarly journals Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

2020 ◽  
Vol 175 (1) ◽  
pp. 64-74 ◽  
Author(s):  
Nivedita Banerjee ◽  
Hui Wang ◽  
Gangduo Wang ◽  
M Firoze Khan
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Autoimmune Response ◽  
Mediated Effects ◽  
Antioxidant Gene Expression ◽  
Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

Multi-Axial Mechanical Stimulation of HUVECs Demonstrates That Combined Loading is not Equivalent to the Superposition of Individual Wall Shear Stress and Tensile Hoop Stress Components

2009 ◽  
Vol 131 (8) ◽  
Author(s):  
Liam T. Breen ◽  
Peter E. McHugh ◽  
Bruce P. Murphy
Keyword(s):  
Shear Stress ◽  
Wall Shear Stress ◽  
Cellular Response ◽  
Umbilical Vein ◽  
Combined Loading ◽  
Hoop Strain ◽  
Hemodynamic Forces ◽  
Testing Period ◽  
Wall Shear

Over the past 25 years, many laboratory based bioreactors have been used to study the cellular response to hemodynamic forces. The vast majority of these studies have focused on the effect of a single isolated hemodynamic force, generally consisting of a wall shear stress (WSS) or a tensile hoop strain (THS). However, investigating the cellular response to a single isolated force does not accurately represent the true in vivo situation, where a number of forces are acting simultaneously. This study used a novel bioreactor to investigate the cellular response of human umbilical vein endothelial cells (HUVECs) exposed to a combination of steady WSS and a range of cyclic THS. HUVECs exposed to a range of cyclic THS (0–12%), over a 12 h testing period, expressed an upregulation of both ICAM-1 and VCAM-1. HUVECs exposed to a steady WSS (0 dynes/cm2 and 25 dynes/cm2), over a 12 h testing period, also exhibited an ICAM-1 upregulation but a VCAM-1 downregulation, where the greatest level of WSS stimulus resulted in the largest upregulation and downregulation of ICAM-1 and VCAM-1, respectively. A number of HUVEC samples were exposed to a high steady WSS (25 dynes/cm2) combined with a range of cyclic THS (0–4%, 0–8%, and 0–12%) for a 12 h testing period. The initial ICAM-1 upregulation, due to the WSS alone, was downregulated with the addition of a cyclic THS. It was observed that the largest THS (0–12%) had the greatest reducing effect on the ICAM-1 upregulation. Similarly, the initial VCAM-1 downregulation, due to the high steady WSS alone, was further downregulated with the addition of a cyclic THS. A similar outcome was observed when HUVEC samples were exposed to a low steady WSS combined with a range of cyclic THS. However, the addition of a THS to the low WSS did not result in an expected ICAM-1 downregulation. In fact, it resulted in a trend of unexpected ICAM-1 upregulation. The unexpected cellular response to the combination of a steady WSS and a cyclic THS demonstrates that such a response could not be determined by simply superimposing the cellular responses exhibited by ECs exposed to a steady WSS and a cyclic THS that were applied in isolation.

scholarly journals Identification and Characterization of SAP25, a Novel Component of the mSin3 Corepressor Complex

2006 ◽  
Vol 26 (4) ◽  
pp. 1386-1397 ◽  
Author(s):  
Yuzuru Shiio ◽  
David W. Rose ◽  
Radin Aur ◽  
Sam Donohoe ◽  
Ruedi Aebersold ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Histone Deacetylases ◽  
Subcellular Location ◽  
Nuclear Bodies ◽  
Nuclear Accumulation ◽  
Affinity Tag ◽  
Pml Nuclear Bodies ◽  
Corepressor Complex

ABSTRACT The transcriptional corepressor mSin3 is associated with histone deacetylases (HDACs) and is utilized by many DNA-binding transcriptional repressors. We have cloned and characterized a novel mSin3A-binding protein, SAP25. SAP25 binds to the PAH1 domain of mSin3A, associates with the mSin3A-HDAC complex in vivo, and represses transcription when tethered to DNA. SAP25 is required for mSin3A-mediated, but not N-CoR-mediated, repression. SAP25 is a nucleocytoplasmic shuttling protein, actively exported from the nucleus by a CRM1-dependent mechanism. A fraction of SAP25 is located in promyelocytic leukemia protein (PML) nuclear bodies, and PML induces a striking nuclear accumulation of SAP25. An isotope-coded affinity tag quantitative proteomic analysis of the SAP25 complex revealed that SAP25 is associated with several components of the mSin3 complex, nuclear export machinery, and regulators of transcription and cell cycle. These results suggest that SAP25 is a novel core component of the mSin3 corepressor complex whose subcellular location is regulated by PML.

scholarly journals Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

2017 ◽  
Vol 214 (3) ◽  
pp. 569-578 ◽  
Author(s):  
Hilmar Bading
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Histone Deacetylases ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cell Loss ◽  
Nuclear Accumulation ◽  
Receptor Signaling ◽  
Element Binding Protein ◽  
Responsive Element

Activation of extrasynaptic N-methyl-d-aspartate (NMDA) receptors causes neurodegeneration and cell death. The disease mechanism involves a pathological triad consisting of mitochondrial dysfunction, loss of integrity of neuronal structures and connectivity, and disruption of excitation–transcription coupling caused by CREB (cyclic adenosine monophosphate–responsive element-binding protein) shut-off and nuclear accumulation of class IIa histone deacetylases. Interdependency within the triad fuels an accelerating disease progression that culminates in failure of mitochondrial energy production and cell loss. Both acute and slowly progressive neurodegenerative conditions, including stroke, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, share increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. Six areas of therapeutic objectives are defined, based on which a broadly applicable combination therapy is proposed to combat the pathological triad of extrasynaptic NMDA receptor signaling that is common to many neurodegenerative diseases.

Abstract 489: The Role of Hemodynamics in Modulating p120 and Kaiso Expression and Activity in Atherogenesis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Devin L Weinberg ◽  
Andrew W Pryor ◽  
Christin A Hamilton ◽  
Brett R Blackman
Keyword(s):  
Gene Expression ◽  
Inflammatory Marker ◽  
Adherens Junction ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
P120 Catenin ◽  
Hemodynamic Forces ◽  
Hemodynamic Regulation

Introduction. The generation of atherosclerosis has been shown to be a non-random process, with endothelial cells (ECs) in regions of disturbed hemodynamics developing an atheroprone (pro-inflammatory) phenotype. While a great deal of research has focused on hemodynamic regulation of EC phenotype, the mechanisms that mediate ECs’ response to local shear stress environment remain elusive. p120-catenin (p120) and its transcription factor binding partner Kaiso are expressed in ECs and possess a variety of functions that potentially contribute to the hemodynamic regulation of EC phenotype in atherosclerosis. Specifically, p120 has been shown to regulate adherens junction stability and regulate gene transcription through interaction with Kaiso. Hypothesis. We hypothesize hemodynamic forces modulate the activity of p120 and Kaiso in a manner that alters local endothelial susceptibility to atherogenesis. Methods. Atheroprone/protective hemodynamic profiles obtained by human carotid artery imaging were applied to human ECs in vitro . Protein/gene expression was then analyzed by Western blot, RT-PCR, and imaging. To determine Kaiso-dependent regulation of target gene expression, siRNAs were used to knockdown Kaiso expression. For in vivo validation, vasculature from Apolipoprotein E -/- mice was isolated, fixed, and stained. Results. In vitro, atheroprotective flow upregulates p120 expression and increases its junctional continuity and nuclear accumulation. There is a flow-dependent increase in Kaiso expression over time in both flow conditions, but p120/Kaiso interaction is increased under atheroprone flow. Kaiso knockdown under protective flow results in decreased expression of the anti-inflammatory genes eNOS (0.49 fold) and KLF2 (0.68 fold) and increased expression of the inflammatory marker VCAM (1.44 fold), suggesting a previously unknown anti-atherogenic function of Kaiso. In preliminary mouse studies, Kaiso is expressed in ECs overlying both healthy and diseased regions, as well as being highly expressed within the lesions. Conclusions. p120 and Kaiso expression are regulated in a flow-dependent manner and are potentially a mechanism by which hemodynamics modulate susceptibility to atherogenesis.

The Adaptive Response of Endothelial Transcription to Increased Shear Stress In Vitro

2010 ◽  
Author(s):  
Ji Zhang ◽  
Morton H. Friedman
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Adaptive Response ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Morphological Changes ◽  
Substantial Effect ◽  
Endothelial Phenotype

Previous studies have shown a substantial effect of shear stress on endothelial phenotype and functions such as production of nitric oxide, secretion of growth factors, inflammatory responses, production of reactive oxygen species, permeability to macromolecules and cytoskeletal remodeling [1–3]. However, the dynamics of the endothelial adaptive response to changes in shear stress are largely unknown. The response of vascular endothelial cells to alterations in shear stress is an essential component of normal endothelial physiology, since local shear stress can be altered in vivo by the global hemodynamic changes that are caused by daily activities such as exercise, sleep, smoking and stress. The duration of these changes ranges from minutes to hours. When adapting to the altered shear stress, endothelial cells undergo a series of structural remodeling and morphological changes, and a transient alteration of endothelial phenotype will be induced. An understanding of the transient regulation of endothelial phenotype will not only improve our knowledge of normal endothelial physiology but also yield insights into mechanisms underlying atherogenesis.

Gene Expression Profiles of Arterial Endothelial Cells in Response to Increased Shear Stress In Vivo

2010 ◽  
Author(s):  
Ji Zhang ◽  
Kelley A. Burridge ◽  
Morton H. Friedman
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Phenotypic Change ◽  
Unidirectional Flow ◽  
Hemodynamic Variables ◽  
Endothelial Response ◽  
Local Shear

Endothelial cells in vivo are believed to adapt to local hemodynamics in regions with largely unidirectional flow [1] and develop a quiescent phenotype. However, the local shear stress is altered occasionally by changes in global hemodynamic variables, such as heart rate and flow rate. These changes are caused by a number of normal physiologic events, such as exercise, smoking, sleep, stress and digestion. The duration of these changes ranges from minutes to hours, and endothelial cells undergo structural remodeling and phenotypic transformation in order to adapt to the altered shear stress. During the adaptive response, the dynamics of endothelial phenotypic change adds a new dimension to the endothelial response to shear stress.

HDAC4 mediates development of hypertension via vascular inflammation in spontaneous hypertensive rats

2012 ◽  
Vol 302 (9) ◽  
pp. H1894-H1904 ◽  
Author(s):  
Tatsuya Usui ◽  
Muneyoshi Okada ◽  
Wataru Mizuno ◽  
Mayuko Oda ◽  
Natsuki Ide ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Mesenteric Artery ◽  
Inflammatory Responses ◽  
Trichostatin A ◽  
Vascular Inflammation ◽  
Ros Production ◽  
Hypertensive Rats ◽  
Long Term Treatment ◽  
Wistar Kyoto

Histone deacetylases (HDACs) are transcriptional corepressors. Our recent study demonstrated that HDAC4 protein specifically increases in mesenteric artery from spontaneous hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY). Vascular inflammation is important for pathogenesis of hypertension. We examined whether HDAC4 affects vascular inflammatory responses and promotes hypertension. In vivo, blood pressure, reactive oxygen species (ROS) production, and VCAM-1 expression in isolated mesenteric artery were elevated in young SHR (7 wk old) compared with age-matched WKY, which were prevented by long-term treatment of SHR with an HDACs inhibitor, trichostatin A (TSA; 500 μg·kg−1·day−1 for 3 wk). In isolated mesenteric artery, the increased angiotensin II-induced contraction in SHR was reversed by TSA. The endothelium-dependent relaxation induced by ACh in SHR was augmented by TSA. In cultured rat mesenteric arterial smooth muscle cells (SMCs), expression of HDAC4 mRNA and protein was increased by TNF-α (10 ng/ml). TSA (10 μM, pretreatment for 30 min) inhibited VCAM-1 expression and NF-κB phosphorylation induced by TNF (10 ng/ml, 24 h or 20 min) in SMCs. HDAC4 small interfering RNA inhibited TNF-induced monocyte adhesion, VCAM-1 expression, transcriptional activity of NF-κB, and ROS production in SMCs. The present results demonstrated that proinflammatory effects of HDACs may mediate the further development of hypertension in SHR. It is also suggested in cultured vascular SMCs that TNF-induced HDAC4 mediates vascular inflammation likely via VCAM-1 induction through ROS-dependent NF-κB activation.

Sign in / Sign up

Export Citation Format

Share Document