Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

Singh, Pavneet; Zheng, Xi-Long

doi:10.1371/journal.pone.0112120

Cited by 13 publications

(12 citation statements)

References 39 publications

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“…Activation of myocardin transcriptional activity induces expression of the contractile genes and their proteins. Our previous study showed that overexpression of myocardin in human vascular SMCs through the T‐REx system increases contractility of SMCs (Jiang et al, ; Singh and Zheng, ). To determine whether the atrogin‐1 effects were mediated by an increase in myocardin transcriptional activity, we overexpressed the dominant‐negative (DN) myocardin in SMCs using the T‐REx system, as previously described (Jiang et al, ), before ad‐atrogin‐1 treatment and collagen gel lattice contraction assay.…”

Section: Resultsmentioning

confidence: 99%

Atrogin‐1 Increases Smooth Muscle Contractility Through Myocardin Degradation

Singh

Liu

Gui

et al. 2016

Journal Cellular Physiology

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Atrogin-1, an E3 ligase present in skeletal, cardiac and smooth muscle, down-regulates myocardin protein during skeletal muscle differentiation. Myocardin, the master regulator of smooth muscle cell (SMC) differentiation, induces expression of smooth muscle marker genes through its association with serum response factor (SRF), which binds to the CArG box in the promoter. Myocardin undergoes ubiquitylation and proteasomal degradation. Evidence suggests that proteasomal degradation of myocardin is critical for myocardin to exert its transcriptional activity, but there is no report about the E3 ligase responsible for myocardin ubiquitylation and subsequent transactivation. Here, we showed that overexpression of atrogin-1 increased contractility of cultured SMCs and mouse aortic tissues in organ culture. Overexpression of dominant-negative myocardin attenuated the increase in SMC contractility induced by atrogin-1. Atrogin-1 overexpression increased expression of the SM contractile markers while downregulated expression of myocardin protein but not mRNA. Atrogin-1 also ubiquitylated myocardin for proteasomal degradation in vascular SMCs. Deletion studies showed that atrogin-1 directly interacted with myocardin through its amino acids 284-345. Immunostaining studies showed nuclear localization of atrogin-1, myocardin, and the Rpt6 subunit of the 26S proteasome. Atrogin-1 overexpression not only resulted in degradation of myocardin but also increased recruitment of RNA Polymerase II onto the promoters of myocardin target genes. In summary, our results have revealed the roles for atrogin-1 in the regulation of smooth muscle contractility through enhancement of myocardin ubiquitylation/degradation and its transcriptional activity. J. Cell. Physiol. 232: 806-817, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Atrogin‐1 Increases Smooth Muscle Contractility Through Myocardin Degradation

Singh

Liu

Gui

et al. 2016

Journal Cellular Physiology

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“…Many studies have also shown that NF-κB plays a direct role in regulating the expression of contractile VSMC genes. Activation of the NF-κB signalling pathway in VSMCs results in binding of the NF-κB-p65 subunit to the MYOCD promoter, decreasing the expression of myocardin and myocardin-dependent contractile genes (e.g., αSMA/ ACTA2, SM22α/TAGLN, and SMMHC/MYH11; Tang et al, 2008;Yoshida et al, 2013;Singh & Zheng, 2014). Together, these studies suggest that NF-κB inhibition, which specifically affects VSMCs could be a potential therapeutic target.…”

Section: Targeting Vsmc Inflammatory Activationmentioning

confidence: 88%

The role of smooth muscle cells in plaque stability: Therapeutic targeting potential

Harman

Jørgensen

2019

British J Pharmacology

100

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Events responsible for cardiovascular mortality and morbidity are predominantly caused by rupture of "vulnerable" atherosclerotic lesions. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and have historically been considered beneficial for plaque stability. VSMCs constitute the main cellular component of the protective fibrous cap within lesions and are responsible for synthesising strengthgiving extracellular matrix components. However, lineage-tracing experiments in mouse models of atherosclerosis have shown that, in addition to the fibrous cap, VSMCs also give rise to many of the cell types found within the plaque core. In particular, VSMCs generate a substantial fraction of lipid-laden foam cells, and VSMC-derived cells expressing markers of macrophages, osteochondrocyte, and mesenchymal stem cells have been observed within lesions. Here, we review recent studies that have changed our perspective on VSMC function in atherosclerosis and discuss how VSMCs could be targeted to increase plaque stability.

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“…It was previously reported that PCSK9 is expressed in dedifferentiated vascular SMCs (Ding, Liu, Wang, Deng, Fan, Sun, et al, 2015; Z. H. Tang et al, 2019), but how PCSK9 induces SMC dedifferentiation is not completely understood. It is well‐known that activation of nuclear factor‐κB (NF‐κB) is critical for SMC dedifferentiation (Singh & Zheng, 2014; R. H. Tang et al, 2008). In macrophages, our group showed that PCSK9 overexpression activates the NF‐κB pathway (Z. H. Tang et al, 2017).…”

Section: Pcsk9 and Vascular Diseasementioning

confidence: 99%

Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall

Guo

Yan

Gui

et al. 2020

Journal Cellular Physiology

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Proprotein convertase subtilisin/kexin type‐9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low‐density lipoprotein (LDL)‐cholesterol levels by binding to the LDL‐receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain‐of‐function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR‐dependent or ‐independent mechanisms. More recently, several clinical trials have confirmed that anti‐PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all‐cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR‐related proteins, cluster of differentiation family members, epithelial Na+ channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid‐lowering therapy and disease prevention.

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Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

Cited by 13 publications

References 39 publications

Atrogin‐1 Increases Smooth Muscle Contractility Through Myocardin Degradation

Atrogin‐1 Increases Smooth Muscle Contractility Through Myocardin Degradation

The role of smooth muscle cells in plaque stability: Therapeutic targeting potential

Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall

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