Plasticity-related gene-1 inhibits lysophosphatidic acid-induced vascular smooth muscle cell migration and proliferation and prevents neointima formation

2012 ◽  
Vol 303 (10) ◽  
pp. C1104-C1114 ◽  
Author(s):  
Amira Gaaya ◽  
Odette Poirier ◽  
Nathalie Mougenot ◽  
Tiphaine Hery ◽  
Fabrice Atassi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Lysophosphatidic Acid ◽  
Cell Phenotype ◽  
Related Gene ◽  
Neointimal Formation ◽  
Vsmc Proliferation

Plasticity-related gene-1 (PRG-1) protects neuronal cells from lysophosphatidic acid (LPA) effects. In vascular smooth muscle cells (VSMCs), LPA was shown to induce phenotypic modulation in vitro and vascular remodeling in vivo. Thus we explored the role of PRG-1 in modulating VSMC response to LPA. PCR, Western blot, and immunofluorescence experiments showed that PRG-1 is expressed in rat and human vascular media. PRG-1 expression was strongly inhibited in proliferating compared with quiescent VSMCs both in vitro and in vivo (medial vs. neointimal VSMCs), suggesting that PRG-1 expression is dependent on the cell phenotype. In vitro, adenovirus-mediated overexpression of PRG-1 specifically inhibited LPA-induced rat VSMC proliferation and migration but not platelet-derived growth factor-induced proliferation. This effect was abolished by mutation of a conserved histidine in the lipid phosphate phosphatase family that is essential for interaction with lipid phosphates. In vivo, balloon-induced neointimal formation in rat carotid was significantly decreased in vessels infected with PRG-1 adenovirus compared with β-galactosidase adenovirus (−71%; P < 0.05). PRG-1 overexpression abolished the activation of the p42/p44 signaling pathway in LPA-stimulated rat VSMCs in culture and in balloon-injured rat carotids. Taken together, these findings provide the first evidence of a protective role of PRG-1 in the vascular media under pathophysiological conditions.

Role of GADD153 (growth arrest- and DNA damage-inducible gene 153) in vascular smooth muscle cell apoptosis

2001 ◽  
Vol 100 (3) ◽  
pp. 275-281 ◽  
Author(s):  
Michiya IGASE ◽  
Takafumi OKURA ◽  
Michitsugu NAKAMURA ◽  
Yasunori TAKATA ◽  
Yutaka KITAMI ◽  
...  
Keyword(s):  
Dna Damage ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Cell Contact ◽  
Inducible Gene

GADD153 (growth arrest- and DNA damage-inducible gene 153) is expressed at very low levels in growing cells, but is markedly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to genotoxic agents and other growth-arresting situations. Forced expression of GADD153 induces cell cycle arrest in many types of cells. It is also reported that GADD153 is directly associated with apoptosis. Recently we have reported that platelet-derived growth factor (PDGF)-BB induces apoptosis in cultured vascular smooth muscle cells (VSMC), but only when 100% confluency is reached. These results suggested that cell–cell contact inhibition (cell growth arrest) may be a critical factor for induction of VSMC apoptosis by PDGF-BB. In the present study, we explored the role of GADD153, one of a number of growth-arrest-related gene products, in the molecular mechanisms of VSMC apoptosis in vitro and in vivo. GADD153 was markedly induced at both the mRNA and protein levels, in parallel with the induction of VSMC apoptosis, after treatment with PDGF-BB. Moreover, overexpression of GADD153 in VSMC significantly reduced cell viability and induced apoptosis. In the carotid artery balloon injury model in rats, GADD153 protein was expressed in apoptotic VSMC which were positively stained by in situ DNA labelling. These results demonstrate an important role for GADD153 in the molecular mechanisms of VSMC apoptosis.

Abstract 374: Inhibition of Mitochondrial CaMKII Reduces Vascular Smooth Muscle Migration and Neointima Formation and Halts Mitochondrial Mobility

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Emily Nguyen ◽  
Olha Koval ◽  
Isabella Grumbach
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Mitochondrial Fission ◽  
Leading Edge ◽  
Neointima Formation ◽  
Vsmc Proliferation ◽  
Mitochondrial Motility ◽  
And Migration

Background: Restenosis after angioplasty for coronary vascular disease remains a critical problem in cardiovascular medicine. Vascular smooth muscle cell (VSMC) migration and proliferation cause restenosis through neointima formation. Mitochondrial motility is likely necessary for cell proliferation and migration, and is inhibited in microdomains with increased Ca 2+ . The Ca 2+ /calmodulin-dependent kinase II (CaMKII) in mitochondria (mtCaMKII) is proposed to control mitochondrial matrix Ca 2+ uptake through mitochondrial Ca 2+ uniporter (MCU). Thus, we hypothesized that blocking mtCaMKII decreases VSMC migration and neointima formation by decreasing mitochondrial motility. Methods: mtCaMKII was inhibited by expression of the mitochondria-targeted CaMKII inhibitor peptide (CaMKIIN) in a novel transgenic mouse model in smooth muscle only (SM-mtCaMKIIN) or delivered by adenoviral transduction (Ad-mtCaMKIIN). Results: In our models, mtCaMKIIN was detected selectively in mitochondria of VSMC. mtCaMKIIN significantly reduced mitochondrial Ca 2+ current and Ca 2+ content compared to WT in vivo and in vitro. SM-mtCaMKIIN mice showed significantly reduced neointimal area 28 days after endothelial injury (n=8, p<0.05) and fewer proliferating neointimal cells by PCNA staining. In vitro, Ad-mtCaMKIIN mildly reduced VSMC proliferation and mitochondrial ROS production without altering maximal respiration after PDGF treatment. Ad-mtCaMKIIN abolished VSMC migration, as did mitoTEMPO and MCU inhibitor Ru360. Ad-mtCaMKIIN blocked mitochondrial mobility towards the leading edge, while relocation of mitochondria was seen in WT cells 6 h after PDGF treatment. Mitochondrial redistribution was also inhibited by Ru360, but not by mitoTEMPO or cytoplasmic CaMKII inhibition. Mitochondrial fission promotes cell migration. Accordingly, PDGF increased mitochondrial particles in WT VSMC, while mitochondria in Ad-mtCaMKIIN cells were fragmented and unresponsive to PDGF treatment. Conclusions: mtCaMKIIN prevents mitochondrial distribution to the leading edge and reduces VSMC migration and neointima formation. These data suggest mitochondrial Ca 2+ regulation plays an important role in VSMC migration by altering mitochondrial location.

Differential regulation of vascular smooth muscle and endothelial cell proliferation in vitro and in vivo by cAMP/PKA-activated p85αPI3K

2009 ◽  
Vol 297 (6) ◽  
pp. H2015-H2025 ◽  
Author(s):  
Daniele Torella ◽  
Cosimo Gasparri ◽  
Georgina M. Ellison ◽  
Antonio Curcio ◽  
Angelo Leone ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Neointimal Hyperplasia ◽  
Endothelial Cell Proliferation ◽  
Balloon Injury ◽  
Vsmc Proliferation ◽  
Endothelial Regeneration ◽  
Proliferation In Vitro

cAMP inhibits proliferation in most cell types, triggering different and sometimes opposing molecular pathways. p85α (phosphatidylinositol 3-kinase regulatory subunit) is phosphorylated by cAMP/PKA in certain cell lineages, but its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are unknown. In the present study, we evaluated 1) the role of p85α in the integration of cAMP/PKA-dependent signaling on the regulation of VSMC and EC growth in vitro; and 2) the effects of PKA-modified p85α on neointimal hyperplasia and endothelial healing after balloon injury in vivo. Plasmid constructs carrying wild-type and PKA-modified p85α were employed in VSMCs and ECs in vitro and after balloon injury in rat carotid arteries in vivo. cAMP/PKA reduced VSMC proliferation through p85α phosphorylation. Transfected PKA-activated p85α binds p21ras, reducing ERK1/2 activation and VSMC proliferation in vitro. In contrast, EC proliferation inhibition by cAMP is independent from PKA modification of p85α and ERK1/2 inhibition; indeed, PKA-activated p85α did not inhibit per se ERK1/2 activation and proliferation in ECs in vitro. Interestingly, cAMP reduced both VSMC and EC apoptotic death through p85α phosphorylation. Accordingly, PKA-activated p85α triggered Akt activation, reducing both VSMC and EC apoptosis in vitro. Finally, compared with controls, vascular gene transfer of PKA-activated p85α significantly reduced neointimal formation after balloon injury in rats, without inhibiting endothelial regeneration of the injured arterial segment. In conclusions, PKA-activated p85α integrates cAMP/PKA signaling differently in VSMCs and ECs. By reducing neointimal hyperplasia without inhibiting endothelial regeneration, it exerts a protective effect against restenosis after balloon injury.

scholarly journals circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation

2021 ◽  
Vol 8 ◽  
Author(s):  
Peng Kong ◽  
Chang-Lin Li ◽  
Yong-Qing Dou ◽  
Li Cao ◽  
Xiao-Yun Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Nuclear Translocation ◽  
Neointimal Hyperplasia ◽  
Neointimal Formation ◽  
P53 Activation ◽  
The One ◽  
Sirt1 Gene

Vascular smooth muscle cell (VSMC) senescence is a major driver of neointimal formation. We have demonstrated that circ-Sirt1 derived from the SIRT1 gene suppressed VSMC inflammation and neointimal formation. However, the effect of circ-Sirt1 inhibiting inflammation on VSMC senescence during neointimal hyperplasia remains to be elucidated. Here, we showed that circ-Sirt1 was highly expressed in young and healthy arteries, which was decreased in aged arteries and neointima of humans and mice. Overexpression of circ-Sirt1 delayed Ang II-induced VSMC senescence in vitro and ameliorated neointimal hyperplasia in vivo. Mechanically, circ-Sirt1 inhibited p53 activity at the levels of transcription and post-translation modulation. In detail, circ-Sirt1, on the one hand, interacted with and held p53 to block its nuclear translocation, and on the other hand, promoted SIRT1-mediated p53 deacetylation and inactivation. In conclusion, our data suggest that circ-Sirt1 is a novel p53 repressor in response senescence-inducing stimuli, and targeting circ-Sirt1 may be a promising approach to ameliorating aging-related vascular disease.

Abstract 459: O-Linked N-Acetylglucosamine Promotes Vascular Smooth Muscle Cell Dedifferentiation and Intimal Hyperplasia

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ashley J Bauer ◽  
Kristen L Leslie ◽  
Allison C Ostriker ◽  
Kathleen A Martin
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Intimal Hyperplasia ◽  
Transcriptional Repression ◽  
Human Coronary Artery ◽  
Artery Ligation ◽  
Vsmc Proliferation ◽  
Marker Expression

Vascular smooth muscle cells (VSMCs) exhibit a unique phenotypic plasticity that underlies numerous cardiovascular pathologies. Platelet-derived growth factor (PDGF) promotes VSMC dedifferentiation characterized by proliferation and decreased contractile protein expression while the mTORC1 inhibitor and stent therapeutic rapamycin inhibits these effects. The enzyme O-linked N-Acetylglucosamine (O-GlcNAc) Transferase (OGT) adds O-GlcNAc modifications to serine or threonine in proteins and has been implicated in cardiovascular diseases. We hypothesized that OGT may regulate VSMC plasticity. We found that OGT and O-GlcNAc expression were associated with dedifferentiation, as both were decreased by rapamycin, but increased with PDGF treatment in human coronary artery SMCs. Knocking down OGT in vitro increased contractile marker expression at the mRNA and protein levels, including MYH11, CNN, TGLN, and ACTA2, while decreasing VSMC proliferation. Conversely, OGT overexpression inhibited expression of MHY11, CNN, and TGLN. Consistent with a role in dedifferentiation, immunostaining revealed that OGT and O-GlcNAc were increased following femoral artery endothelial denudation injury in C57BL/6 mice. Notably, smooth muscle-specific OGT knockout attenuated neointima formation relative to controls in a carotid artery ligation model of intimal hyperplasia. In conclusion, these findings indicate that PDGF and vascular injury increase OGT expression and O-GlcNAc modifications in SMCs in vitro and in vivo, leading to OGT-dependent transcriptional repression of contractile marker expression and promotion of intimal hyperplasia.

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