scholarly journals Essential role of Orai1 and SARAF in vascular remodeling

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Marta Martín-Bórnez ◽  
Javier Ávila-Medina ◽  
Eva Calderón-Sánchez ◽  
Juan Antonio Rosado ◽  
Antonio Ordoñez-Fernández ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Carotid Arteries ◽  
Regulatory Protein ◽  
Neointima Formation ◽  
Balloon Injury ◽  
Vsmc Proliferation ◽  
Store Operated Calcium Entry ◽  
Molecular Components ◽  
Interfering Rna

Orai1 and STIM1, molecular components of store-operated calcium entry (SOCE), have been associated with vascular smooth muscle cell (VSMC) proliferation in vascular remodeling. Nevertheless, the role of SARAF (SOCE-associated regulatory factor), a regulatory protein involved in STIM1 inhibition, in vascular remodeling has not been examined. The aim of this study is to examine the role of SARAF and Orai1 in VSMC proliferation and neointima formation after balloon injury of rat carotid arteries. Experiments were conducted in an animal model of rat carotid angioplasty to characterize neointima formation. VSMC isolated from rat coronary arteries was also used to examine cell proliferation. The formation of neointima after balloon injury of rat carotid arteries was confirmed by hematoxylin and eosin staining of tissue sections up to 3 wk after surgery. Injured arteries showed significantly higher expression of SARAF, STIM1, and Orai1 compared with control tissues, corroborating the presence of these regulatory proteins in the neointima layer. Proximity ligation and coimmunoprecipitation assays revealed that SARAF interacts with Orai1 in the neointima. Furthermore, selective silencing of SARAF and Orai1 by small interfering RNA (siRNA) inhibited IGF-1–induced VSMC proliferation. Our data suggest that SARAF interacts with Orai1 to modulate SOCE and VSMC proliferation after vascular injury.

scholarly journals Diet-Induced Hyperhomocysteinemia Exacerbates Neointima Formation in Rat Carotid Arteries After Balloon Injury

Circulation ◽  
2001 ◽  
Vol 103 (1) ◽  
pp. 133-139 ◽  
Author(s):  
Hiroyuki Morita ◽  
Hiroki Kurihara ◽  
Shigetaka Yoshida ◽  
Yuichiro Saito ◽  
Takayuki Shindo ◽  
...  
Keyword(s):  
Carotid Arteries ◽  
Neointima Formation ◽  
Balloon Injury

Abstract 497: 5-Methoxytryptophan Protects Against Vascular Remodeling

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yen-Chun Ho ◽  
Meng-Ling Wu ◽  
Chen-Hsuan Su ◽  
Cheng-Chin Kuo ◽  
Kenneth K Wu ◽  
...  
Keyword(s):  
Vascular Disease ◽  
P38 Mapk ◽  
Vessel Wall ◽  
Neointima Formation ◽  
Phenotypic Modulation ◽  
Mapk Activation ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Vascular smooth muscle cells (VSMCs) in the blood vessel wall exhibit a differentiated phenotype; their main function is contraction and to regulate vascular tone. In response to injury, VSMCs undergo a phenotypic transition whereby they proliferate and migrate from the medial layer into the intima, contributing to lesion formation and atherosclerosis. 5-methoxytryptophan (5-MTP), a recently identified novel tryptophan metabolite, has been shown to inhibit cancer cell growth, migration, and cancer metastasis. We hypothesized that 5-MTP might play an analogous role in vascular disease as in tumorigenesis. To test our hypothesis, we subjected 12 weeks old C57BL/6 mice to a carotid artery cessation of blood flow model to induce neointima formation. Following surgery, mice were treated with vehicle (PBS) or 100 mg/kg of 5-MTP by intraperitoneal injection 3 times a week. Four weeks later, carotid arteries were harvested for histological analysis. H&E and elastin staining revealed robust neointima in ligated carotids of vehicle-treated mice. In contrast, 5-MTP significantly attenuated neointima formation. Given that proinflammatory cytokine interleukin 1 beta (IL-1β) is increased in the injured vessel wall, we examined whether IL-1β affected VSMC phenotypic modulation. Indeed, IL-1β downregulated VSMC marker SM α-actin expression and increased VSMC proliferation and migration. Importantly, in VSMCs, 5-MTP attenuated IL-1β-mediated SM α-actin downregulation, proliferation, and migration, suggesting a potential role of 5-MTP in controlling VSMC phenotypic modulation. Furthermore, 5-MTP inhibited IL-1β-mediated p38 MAPK activation. Inhibiting p38 MAPK activation by SB203580 dose-dependently decreased IL-1β-induced VSMC proliferation. Taken together, our results suggest an important role of 5-MTP in vascular disease.

scholarly journals Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

2020 ◽  
Vol 14 ◽  
Author(s):  
Isis Zhang ◽  
Huijuan Hu
Keyword(s):  
Nervous System ◽  
Calcium Channels ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Physiological Role ◽  
The Body ◽  
Store Operated Calcium Entry ◽  
Important Pathway ◽  
Molecular Components

Store-operated calcium channels (SOCs) are widely expressed in excitatory and non-excitatory cells where they mediate significant store-operated calcium entry (SOCE), an important pathway for calcium signaling throughout the body. While the activity of SOCs has been well studied in non-excitable cells, attention has turned to their role in neurons and glia in recent years. In particular, the role of SOCs in the nervous system has been extensively investigated, with links to their dysregulation found in a wide variety of neurological diseases from Alzheimer’s disease (AD) to pain. In this review, we provide an overview of their molecular components, expression, and physiological role in the nervous system and describe how the dysregulation of those roles could potentially lead to various neurological disorders. Although further studies are still needed to understand how SOCs are activated under physiological conditions and how they are linked to pathological states, growing evidence indicates that SOCs are important players in neurological disorders and could be potential new targets for therapies. While the role of SOCE in the nervous system continues to be multifaceted and controversial, the study of SOCs provides a potentially fruitful avenue into better understanding the nervous system and its pathologies.

Abstract 570: Cystathionine γ-Lyase Modulates Flow-dependent Vascular Remodeling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Shuai Yuan ◽  
Arif Yurdagul ◽  
Jonette M Green ◽  
Sibile Pardue ◽  
Christopher G Kevil ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Remodeling ◽  
Oscillatory Flow ◽  
Carotid Arteries ◽  
Dependent Manner ◽  
Disturbed Flow ◽  
Sulfane Sulfur ◽  
Nitrite Level

Disturbed flow causes endothelial dysfunction and development of atherosclerotic lesions. The gaseous signaling molecule H 2 S and cystathionine γ-lyase (CSE), its major enzymatic source in the vasculature, protect against cardiovascular diseases including atherosclerosis, peripheral artery disease, and cardiac ischemia in a nitric oxide (NO) dependent manner. Therefore, we sought to investigate the role of CSE in the endothelial response to disturbed flow. Wild-type C57Bl/6 (WT) and CSE knockout (CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid with the right carotid serving as an internal control. Additionally, endothelial cells isolated from WT and CSE-/- mice were exposed to oscillatory flow, a model of disturbed flow, in vitro. While disturbed flow decreased endothelial CSE mRNA expression, CSE protein expression showed strong induction under disturbed flow conditions both in vitro and in vivo. This induction correlated with enhanced free sulfide and sulfane sulfur production in WT but not in CSE-/- mice. Intimal mRNA isolated 2 days post-ligation showed increased VCAM-1 and ICAM-1 expression in WT mice which was prevented in CSE-/- mice. Similarly, endothelial cells isolated from CSE-/- mice show reduced NF-B activation and proinflammatory gene expression in response to oscillatory flow in vitro. Morphometric analysis of carotid arteries collected 7 days post-ligation revealed reduced macrophage infiltration and medial thickening in the ligated carotid of CSE-/- mice. Interestingly, ligation increased the carotid nitrite level in WT mice but not in CSE-/- mice. However, nitrite level of the non-ligated carotid was significantly higher in the CSE-/- mice compared to WT mice. Shear induced phosphorylation of eNOS Ser1179 in vitro was not different between WT and CSE knockout endothelial cells, suggesting alternative regulatory mechanisms. Collectively, CSE in mouse carotid arteries plays a critical role in flow dependent vascular remodeling, which may be mediated by CSE derived free sulfide and sulfane sulfur. CSE deficiency completely inhibits disturbed flow-induced NF-κB activation and macrophage recruitment, consistent with the role of inflammation in vascular remodeling.

scholarly journals H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation

2021 ◽  
Author(s):  
Di Yang ◽  
Zhenghua Su ◽  
Gang Wei ◽  
Fen Long ◽  
Yichun Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Neointimal Hyperplasia ◽  
Neointima Formation ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
And Migration ◽  
Proliferation And Migration

Objective: Smyd3 (SET and MYND domain-containing protein 3) is an H3K4 (histone H3 lysine 4) dimethyltransferase and trimethyltransferase that activates the transcription of oncogenes and cell cycle genes in human cancer cells. We discovered its overexpression in proliferative vascular smooth muscle cells (VSMCs). However, whether Smyd3 plays a role in vascular remodeling remains unanswered. The objective of this study is to investigate the role and underlying mechanism of Smyd3 in phenotypic transition of VSMCs (such as proliferation and migration) and vascular remodeling (such as neointima formation). Approach and Results: We discovered upregulation of Smyd3 in both PDGF (platelet-derived growth factor) BB–induced vascular cell proliferation model and balloon injury–induced neointima formation model. Knockdown of Smyd3 or blockade of its enzymatic activity suppressed VSMCs proliferation and migration ability, whereas Smyd3 overexpression promoted VSMC migration and proliferation. Mechanistically, RNA-seq and ChIP-seq analysis revealed Smyd3 promoted neointimal formation by directly binding and increasing H3K4me3 to the promoter regions of target genes that are associated with cell proliferation and migration, cell cycle control. Furthermore, knockout of Smyd3 in mice profoundly suppressed carotid artery ligation–induced neointimal hyperplasia, consistently, local knocking down Smyd3 in rats relieved balloon injury–induced neointimal formation, while restored VSMC contractile protein expression, suggesting that Smyd3 plays a critical role in vivo. Conclusions: Our results demonstrate that Smyd3 promotes VSMC proliferation and migration during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

Abstract 338: p55γ Suppresses VSMC Proliferation and Neointimal Formation

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chun-Mei Cao ◽  
Ning Xie ◽  
Yuan Yao ◽  
Yan Zhang ◽  
Rui-Ping Xiao
Keyword(s):  
Carotid Arteries ◽  
P53 Protein ◽  
Vascular Diseases ◽  
Regulatory Subunit ◽  
Quiescent State ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
Adenoviral Gene Transfer ◽  
Vsmc Proliferation

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to various vascular diseases, but the factors that maintain VSMCs in a quiescent state remain poor understood. Phosphatidylinositol 3 kinases (PI3Ks) are important protein kinases that regulate vascular cell proliferation, but the biological and pathological functions of p55γ, a regulatory subunit of PI3K, and its regulation in the cardiovascular system are completely unknown. We aimed to determine the relationship between p55γ and vascular proliferation and neointimal formation. In the present study, we have demonstrated that p55γ expression is markedly downregulated in primary cultured VSMCs in response to mitogenic stimulation and in carotid arteries after balloon injury, and that overexpression p55γ profoundly inhibits mitogenic stimuli and injury induced VSMC proliferation as well as neointimal formation. p55γ overexpression inhibited, whereas knockdown of p55γ promoted PDGF-BB- and serum-induced VSMC proliferation. Importantly, in vivo adenoviral gene transfer of p55γ into carotid arteries attenuated, while knockdown of p55γenhanced balloon injury-induced neointimal formation. Furthermore, p55γ sequentially upregulated p53 and p21, resulting in cell-cycle arrest in S phase; knockdown of either p53 or p21 blocked p55γ-induced VSMC growth arrest. Mechanistically, p55γ interacted with and stabilized p53 protein by blocking MDM2-mediated p53 ubiquitination and degradation, subsequently activating its target gene p21. Concurrently, p55γ upregulated Bcl-xl expression, which counterbalanced p53-mediated apoptosis. These findings mark p55γ as a novel upstream regulator of the p53-p21 signaling pathway which negatively regulates VSMC proliferation, suggesting that malfunction of p55γ may trigger vascular proliferative disorders. * Correspondence to Chun-Mei Cao ([email protected]) or Rui-Ping Xiao ([email protected]).

scholarly journals Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells

2018 ◽  
Vol 115 (37) ◽  
pp. E8660-E8667 ◽  
Author(s):  
Abu Shufian Ishtiaq Ahmed ◽  
Kunzhe Dong ◽  
Jinhua Liu ◽  
Tong Wen ◽  
Luyi Yu ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Phenotypic Switching ◽  
Specific Gene ◽  
Neointima Formation ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

In response to vascular injury, vascular smooth muscle cells (VSMCs) may switch from a contractile to a proliferative phenotype thereby contributing to neointima formation. Previous studies showed that the long noncoding RNA (lncRNA) NEAT1 is critical for paraspeckle formation and tumorigenesis by promoting cell proliferation and migration. However, the role of NEAT1 in VSMC phenotypic modulation is unknown. Herein we showed that NEAT1 expression was induced in VSMCs during phenotypic switching in vivo and in vitro. Silencing NEAT1 in VSMCs resulted in enhanced expression of SM-specific genes while attenuating VSMC proliferation and migration. Conversely, overexpression of NEAT1 in VSMCs had opposite effects. These in vitro findings were further supported by in vivo studies in which NEAT1 knockout mice exhibited significantly decreased neointima formation following vascular injury, due to attenuated VSMC proliferation. Mechanistic studies demonstrated that NEAT1 sequesters the key chromatin modifier WDR5 (WD Repeat Domain 5) from SM-specific gene loci, thereby initiating an epigenetic “off” state, resulting in down-regulation of SM-specific gene expression. Taken together, we demonstrated an unexpected role of the lncRNA NEAT1 in regulating phenotypic switching by repressing SM-contractile gene expression through an epigenetic regulatory mechanism. Our data suggest that NEAT1 is a therapeutic target for treating occlusive vascular diseases.

Janus Kinase 3 Deficiency Promotes Vascular Reendothelialization

2021 ◽  
Author(s):  
Yung-Chun Wang ◽  
Dunpeng Cai ◽  
Xiao-Bing Cui ◽  
Ya-Hui Chuang ◽  
William P. Fay ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Injury ◽  
Intimal Hyperplasia ◽  
Carotid Arteries ◽  
Muscle Cells ◽  
Janus Kinase ◽  
Balloon Injury ◽  
Janus Kinase 3

Objective: The objective of this study is to determine the role of JAK3 (Janus kinase 3) in reendothelialization after vascular injury. Methods and Results: By using mouse carotid artery wire injury and rat balloon injury model, we found that JAK3 regulates reendothelialization and endothelial cell proliferation after vascular injury. JAK3 and phospho-JAK3 levels were increased in neointimal smooth muscle cells in response to vascular injury in mice. JAK3 deficiency dramatically attenuated the injury-induced intimal hyperplasia in carotid arteries of both male and female mice. Importantly, JAK3 deficiency caused an increased rate of reendothelialization following mechanical injury. Likewise, knockdown of JAK3 in medial smooth muscle cells elicited an accelerated reendothelialization with reduced intimal hyperplasia following balloon injury in rat carotid arteries. Interestingly, knockdown of JAK3 restored the expression of smooth muscle cell contractile protein smooth muscle α-actin in injury-induced intimal smooth muscle cells while increased the proliferating endothelial cells in the intima area. Conclusions: Our results demonstrate a novel role of JAK3 in the regeneration of endothelium after vascular injury, which may provide a new strategy to enhance reendothelialization while suppressing neointimal formation for effective vascular repair from injury.

scholarly journals Lysophosphatidic acid-induced vascular neointimal formation in mouse carotid arteries is mediated by the matricellular protein CCN1/Cyr61

2016 ◽  
Vol 311 (6) ◽  
pp. C975-C984 ◽  
Author(s):  
Feng Hao ◽  
Fuqiang Zhang ◽  
Daniel Dongwei Wu ◽  
Dong An ◽  
Jing Shi ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Vascular Remodeling ◽  
Carotid Arteries ◽  
In Vivo Model ◽  
Matricellular Protein ◽  
Neointimal Formation ◽  
Lpa Receptor

Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low-density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation. By using LPA infusion of carotid artery in a mouse model, we demonstrated that LPA highly induced CCN1 expression (approximately six- to sevenfold) in neointimal lesions. Downregulation of CCN1 expression with the specific CCN1 siRNA in carotid arteries blocked LPA-induced neointimal formation, indicating that CCN1 is essential in LPA-induced neointimal formation. We then used LPA receptor knockout (LPA1−/−, LPA2−/−, and LPA3−/−) mice to examine LPA receptor function in CCN1 expression in vivo and in LPA-induced neointimal formation. Our data reveal that LPA1 deficiency, but not LPA2 or LPA3 deficiency, prevents LPA-induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA1 deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA1 is the major mediator for LPA-induced vascular remodeling. Our in vivo model of LPA-induced neointimal formation established a key role of the ECM protein CCN1 in mediating LPA-induced neointimal formation. Our data support the notion that the LPA1-CCN1 axis may be the central control for SMC migration and vascular remodeling. CCN1 may serve as an important vascular disease marker and potential target for vascular therapeutic intervention.

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