scholarly journals Mitochondrial Protein Poldip2 (Polymerase Delta Interacting Protein 2) Controls Vascular Smooth Muscle Differentiated Phenotype by O-Linked GlcNAc (N-Acetylglucosamine) Transferase–Dependent Inhibition of a Ubiquitin Proteasome System

2020 ◽  
Vol 126 (1) ◽  
pp. 41-56 ◽  
Author(s):  
Felipe Paredes ◽  
Holly C. Williams ◽  
Raymundo A. Quintana ◽  
Alejandra San Martin
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tricarboxylic Acid Cycle ◽  
Neointimal Hyperplasia ◽  
Mitochondrial Protein ◽  
Ubiquitin Proteasome System ◽  
Protein Glycosylation ◽  
Interacting Protein ◽  
Ubiquitin Proteasome ◽  
Acetylglucosamine Transferase

Rationale: The mitochondrial Poldip2 (protein polymerase interacting protein 2) is required for the activity of the tricarboxylic acid cycle. As a consequence, Poldip2 deficiency induces metabolic reprograming with repressed mitochondrial respiration and increased glycolytic activity. Though homozygous deletion of Poldip2 is lethal, heterozygous mice are viable and show protection against aneurysm and injury-induced neointimal hyperplasia, diseases linked to loss of vascular smooth muscle differentiation. Thus, we hypothesize that the metabolic reprograming induced by Poldip2 deficiency controls VSMC differentiation. Objective: To determine the role of Poldip2-mediated metabolic reprograming in phenotypic modulation of VSMC. Methods and Results: We show that Poldip2 deficiency in vascular smooth muscle in vitro and in vivo induces the expression of the SRF (serum response factor), myocardin, and MRTFA (myocardin-related transcription factor A) and dramatically represses KLF4 (Krüppel-like factor 4). Consequently, Poldip2-deficient VSMC and mouse aorta express high levels of contractile proteins and, more significantly, these cells do not dedifferentiate nor acquire macrophage-like characteristics when exposed to cholesterol or PDGF (platelet-derived growth factor). Regarding the mechanism, we found that Poldip2 deficiency upregulates the hexosamine biosynthetic pathway and OGT (O-linked N-acetylglucosamine transferase)-mediated protein O-GlcNAcylation. Increased protein glycosylation causes the inhibition of a nuclear ubiquitin proteasome system responsible for SRF stabilization and KLF4 repression and is required for the establishment of the differentiated phenotype in Poldip2-deficient cells. Conclusions: Our data show that Poldip2 deficiency induces a highly differentiated phenotype in VSMCs through a mechanism that involves regulation of metabolism and proteostasis. Additionally, our study positions mitochondria-initiated signaling as key element of the VSMC differentiation programs that can be targeted to modulate VSMC phenotype during vascular diseases.

S-adenosylmethionine Inhibits Ubiquitin-Proteasome System In Vitro and on Rat Vascular Smooth Muscle Cells

2008 ◽  
Vol 15 (1) ◽  
pp. 58-62 ◽  
Author(s):  
Fabrizio D'Anselmi ◽  
Alessandra Cucina ◽  
Giuseppe Cavallaro ◽  
Mariano Bizzarri ◽  
Rosaria Cavallaro ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

Micro-RNA Regulation of Vascular Smooth Muscle Cells and Its Significance in Cardiovascular Diseases

2021 ◽  
Author(s):  
Duong Ngoc Diem Nguyen ◽  
William M Chilian ◽  
Shamsul Mohd Zain ◽  
Muhammad Fauzi Daud ◽  
Yuh Fen Pung
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Intracellular Signaling ◽  
Neointimal Hyperplasia ◽  
Muscle Cells ◽  
Micro Rna ◽  
Phenotypic Switching ◽  
Micro Rnas

Cardiovascular disease (CVD) is among the leading causes of death worldwide. Micro-RNAs (miRNAs), regulatory molecules that repress protein expression, have attracted considerable attention in CVD research. The vasculature plays a big role in CVD development and progression and dysregulation of vascular cells underlies the root of many vascular diseases. This review provides a brief introduction of the biogenesis of miRNAs and exosomes, followed by overview of the regulatory mechanisms of miRNAs in vascular smooth muscle cells (VSMCs) intracellular signaling during phenotypic switching, senescence, calcification and neointimal hyperplasia. Evidence of extracellular signaling of VSMCs and other cells via exosomal and circulating miRNAs was also presented. Lastly, current drawbacks and limitations of miRNA studies in CVD research and potential ways to overcome these disadvantages were discussed in detail. In-depth understanding of VSMC regulation via miRNAs will add substantial knowledge and advance research in diagnosis, disease progression and/or miRNA-derived therapeutic approaches in CVD research.

Femoral artery neointimal hyperplasia is reduced after wire injury in Ref-1+/− mice

2007 ◽  
Vol 292 (1) ◽  
pp. H516-H521 ◽  
Author(s):  
David L. Basi ◽  
Neeta Adhikari ◽  
Ami Mariash ◽  
Qinglu Li ◽  
Esther Kao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Femoral Artery ◽  
Cellular Response ◽  
Fas Ligand ◽  
Neointimal Hyperplasia ◽  
Muscle Cells ◽  
Wild Type

Redox factor-1 (Ref-1) is a multifunctional protein that regulates redox, DNA repair, and the response to cell stress. We previously demonstrated that Ref-1+/− mice exhibit a significantly reduced Ref-1 mRNA and protein levels within the vasculature, which are associated with increased oxidative stress. The goal of this study was to test the hypothesis that partial loss of Ref-1 altered the cellular response to vascular injury. Fourteen days after femoral artery wire injury, we found that vessel intima-to-media ratio was significantly reduced in Ref-1+/− mice compared with that in wild-type mice ( P < 0.01). Bromodeoxyuridine labeling and transferase-mediated dUTP nick-end labeling staining at 14 days did not differ in the Ref-1+/− mice. In vitro studies found no significant changes in either serum-induced proliferation or baseline apoptosis in Ref-1+/− vascular smooth muscle cells. Exposure to Fas ligand; however, did result in increased susceptibility of Ref-1+/− vascular smooth muscle cells to apoptosis ( P < 0.001). Ref-1+/− mice exhibited an increase in circulating baseline levels of IL-10, IL-1α, and VEGF compared with those in wild-type mice but a marked impairment in these pathways in response to injury. In sum, loss of a single allele of Ref-1 is sufficient to reduce intimal lesion formation and to alter circulating cytokine and growth factor expression.

scholarly journals Jujuboside B Inhibits Neointimal Hyperplasia and Prevents Vascular Smooth Muscle Cell Dedifferentiation, Proliferation, and Migration via Activation of AMPK/PPAR-γ Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Zaixiong Ji ◽  
Jiaqi Li ◽  
Jianbo Wang
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Neointimal Hyperplasia ◽  
Muscle Cells ◽  
Cell Dedifferentiation ◽  
Ppar Γ ◽  
And Migration ◽  
Proliferation And Migration

The uncontrolled proliferation and migration of vascular smooth muscle cells is a critical step in the pathological process of restenosis caused by vascular intimal hyperplasia. Jujuboside B (JB) is one of the main biologically active ingredients extracted from the seeds of Zizyphus jujuba (SZJ), which has the properties of anti-platelet aggregation and reducing vascular tension. However, its effects on restenosis after vascular intervention caused by VSMCs proliferation and migration remain still unknown. Herein, we present novel data showing that JB treatment could significantly reduce the neointimal hyperplasia of balloon-damaged blood vessels in Sprague-Dawley (SD) rats. In cultured VSMCs, JB pretreatment significantly reduced cell dedifferentiation, proliferation, and migration induced by platelet-derived growth factor-BB (PDGF-BB). JB attenuated autophagy and reactive oxygen species (ROS) production stimulated by PDGF-BB. Besides, JB promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Notably, inhibition of AMPK and PPAR-γ partially reversed the ability of JB to resist the proliferation and migration of VSMCs. Taken as a whole, our findings reveal for the first time the anti-restenosis properties of JB in vivo and in vitro after the endovascular intervention. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation, and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway. These results indicate that JB might be a promising clinical candidate drug against in-stent restenosis, which provides a reference for further research on the prevention and treatment of vascular-related diseases.

Abstract 31: Resolvin D1 Attenuates PDGF-induced Vascular Smooth Muscle Cell Migration via the cAMP Pathway

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Giorgio Mottola ◽  
Bian Wu ◽  
Anuran Chatterjee ◽  
Mian Chen ◽  
Michael S Conte
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Neointimal Hyperplasia ◽  
Lipid Mediator ◽  
Resolvin D1 ◽  
Scratch Assay ◽  
Migratory Activity ◽  
Downstream Signaling ◽  
Rac1 Activity ◽  
Camp Levels

Introduction: Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator (SPM), attenuates migration in vascular smooth muscle cells (VSMC), which is critical to the development of neointimal hyperplasia. SPM are known to interact with G-protein coupled receptors (GPCR). We sought to investigate the pathways by which RvD1 influences VSMC migration. Methods: VSMC were harvested from human saphenous veins. cAMP levels were measured via ELISA in the absence or presence of RvD1 receptor (ALX, GPR32) blockers. NF449, a G s -protein inhibitor, was also used. PDGF-BB (10ng/ml) was used as an agonist in a VSMC scratch assay as well as the receptor blockers. PDGF-BB-induced cytoskeletal changes were measured as aspect ratio after actin staining, and a scratch assay was used to assess migration. PDGF-induced Rac1 activity was measured via ELISA; VASP phosphorylation was assessed by Western blot and Paxillin translocation by Immunofluorescence. PKA inhibitor Rp-8-Br-cAMP (10μM) was used in the phenotypic and downstream signaling studies. Results: RvD1 treatment (10nM) of VSMC induced a significant acute flux in cAMP levels at 5 minutes (Fig. 1A; n≥3); this increase was abolished by an ALX antagonist (WRW4), the anti-GPR32 blocking Ab, and NF449. RvD1 (10nM) attenuated PDGF-induced VSMC migration (Fig. 1B-C; n≥3), cytoskeletal rearrangements (n=4), Rac1 activation (n≥3) and increased phosphorylation of VASP (n=3). These effects were negated by the addition of Rp-8-Br-cAMP, suggesting cAMP involvement. RvD1’s anti-migratory effect was reversed by blocking ALX or GPR32 (Fig. 1C; n≥8). Conclusion: Our results suggest that RvD1 attenuates VSMC migration by increasing levels of cAMP through ALX and GPR32 via a G s -protein-mediated action. Interference with Rac1, VASP and Paxillin function appear to be important for the anti-migratory activity of RvD1.

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