Stress-induced senescence exaggerates postinjury neointimal formation in the old vasculature

2010 ◽  
Vol 298 (1) ◽  
pp. H66-H74 ◽  
Author(s):  
Sheik J. Khan ◽  
Si Pham ◽  
Yunteo Wei ◽  
Dania Mateo ◽  
Melissa St-Pierre ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Vascular Injury ◽  
Vascular Wall ◽  
Galactosidase Activity ◽  
Neointimal Formation ◽  
Normal Cells ◽  
The Media ◽  
Vascular Senescence

This study aims to demonstrate the role of stress-induced senescence in aged-related neointimal formation. We demonstrated that aging increases senescence-associated β-galactosidase activity (SA-β-Gal) after vascular injury and the subsequent neointimal formation (neointima-to-media ratio: 0.8 ± 0.2 vs. 0.54 ± 0.15) in rats. We found that senescent cells (SA-β-Gal+ p21+) were scattered throughout the media and adventitia of the vascular wall at day 7 after injury and reached their maximum number at day 14. However, senescent cells only persisted in the injured arteries of aged animals until day 30. No senescent cells were observed in the noninjured, contralateral artery. Interestingly, vascular senescent cells accumulated genomic 8-oxo-7,8-dihydrodeoxyguanine, indicating that these cells were under intense oxidative stress. To demonstrate whether senescence worsens intimal hyperplasia after injury, we seeded matrigel-embedded senescent and nonsenescent vascular smooth muscle cells around injured vessels. The neointima was thicker in arteries treated with senescent cells with respect to those that received normal cells (neointima-to-media ratio: 0.41 ± 0.105 vs. 0.26 ± 0.04). In conclusion, these results demonstrate that vascular senescence is not only a consequence of postinjury oxidative stress but is also a worsening factor for neointimal development in the aging vasculature.

Abstract 15037: Novel Role of Kelch-like ECH-associated Protein 1/NF-E2-related Factor 2 System in Vascular Smooth Muscle Cell Apoptosis Following Vascular Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Takashi Ashino ◽  
Masayuki Yamamoto ◽  
Satoshi Numazawa
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Injury ◽  
Neointimal Hyperplasia ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Neointimal Formation ◽  
Quinone Oxidoreductase

Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after vascular injury are a key event in the neointimal hyperplasia followed by vascular occlusive diseases. To maintain vascular functions, the number of VSMCs is tightly controlled by those proliferation and apoptosis during vascular remodeling. Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system plays a critical role in the oxidative stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 function is abrogated in response to oxidative stress, leading to Nrf2 stabilization and coordinated up-regulation of antioxidant genes. We have previously found that Nrf2 plays an important role in neointimal hyperplasia after vascular injury via regulating platelet-derived growth factor-induced reactive oxygen species-dependent VSMC migration; however, the role of Keap1-Nrf2 system in VSMC apoptosis has not been established. Here we show that TUNEL-positive cells are detected in both the layers of neointima and media, both of which observe alpha-smooth muscle actin positive and high Nrf2-expressed cells, 14 days after transluminal arterial injury in mice. Nrf2 deficient mice show decreased TUNEL-positive cells in neointimal and medial areas (60%) and enhanced neointimal formation (I/M ratio: 152%) 14 days after vascular injury compared with the wild-type mice. In VSMCs isolated from the thoracic aorta of rats, depletion of Keap1 with siRNA increases nuclear Nrf2 (685%) and induces its target genes, including NAD(P)H: quinone oxidoreductase-1 (664%) and heme oxygenase-1 (230%). Functionally, Keap1 depletion increase apoptotic morphological features such as cell shrinkage and nuclear condensation (4114%), annexin V binding (512%), and positive TUNEL staining in VSMCs, which is associated with caspase-3/7 activation (576%). Pretransfection of VSMCs with Nrf2 siRNA inhibits apotosis mediated by Keap1 siRNA. In summary, Keap1-Nrf2 system regulates VSMC apoptosis in the process of neointimal formation, thereby inhibiting VSMC hyperproliferation, which may contribute to the development of neointimal hyperplasia after vascular injury.

Essential role of PKC-ζ in normal and angiotensin II-accelerated neointimal growth after vascular injury

2006 ◽  
Vol 291 (4) ◽  
pp. H1602-H1613 ◽  
Author(s):  
Jean-Hugues Parmentier ◽  
Chunxiang Zhang ◽  
Anne Estes ◽  
Susan Schaefer ◽  
Kafait U. Malik
Keyword(s):  
Smooth Muscle ◽  
Vascular Injury ◽  
Critical Role ◽  
Immunohistochemical Analysis ◽  
Vascular Wall ◽  
Ang Ii ◽  
Neointimal Formation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Perivascular Area ◽  
Pkc Ζ

The contribution of atypical protein kinase C (PKC)-ζ to ANG II-accelerated restenosis after endoluminal vascular injury was investigated by using the rat carotid balloon injury model. Exposure of injured arteries to ANG II resulted in an extensive neointimal thickening (1.9 times) compared with vehicle at day 14. Treatment with PKC-ζ antisense, but not scrambled, oligonucleotides reduced neointimal formation observed in the presence or absence of ANG II. Examination of early events (2 days) after injury showed an increase in cellularity in the perivascular area of the artery wall that was transferred to the adventitia and media after exposure to ANG II, events blocked by PKC-ζ antisense, but not scrambled, oligonucleotides. A positive correlation between medial cellularity at day 2 and extent of neointimal growth at day 14 was established. Immunohistochemical analysis showed that upregulation of inflammatory markers after injury, as well as infiltration of ED1+monocytes/macrophages from the perivascular area to the adventitia, was accelerated by ANG II. However, ANG II-stimulated medial increase in cellularity was proliferation independent, and these cells were monocyte chemoattractant protein-1+/vimentin+but ED1−/VCAM−. PKC-ζ is degraded after injury, and inhibition of its neosynthesis in medial vascular smooth muscle cells or in infiltrating cells with PKC-ζ antisense attenuated medial cellularity and expression of inflammation mediators without reversing smooth muscle cell dedifferentiation. Together, these data indicate that PKC-ζ plays a critical role in normal and ANG II-accelerated neointimal growth through a mechanism involving upregulation of inflammatory mediators, leading to cell infiltration in the media of the vascular wall.

The Studies on Biocompatibility of Self-Expanding NiTi Stent and Apoptosis of Smooth Muscle Cells after Stenting

2005 ◽  
Vol 288-289 ◽  
pp. 587-590 ◽  
Author(s):  
Chun Jiang Li ◽  
Yu Feng Zheng ◽  
Chao Li ◽  
Lian Cheng Zhao
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Niti Alloy ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Vessel Remodeling ◽  
Proliferation And Apoptosis ◽  
The Media ◽  
Atherosclerotic Process ◽  
Stent Surface

The biocompatibility of the NiTi alloy self-expanding stent, its dilating effect on the vascular wall, and the apoptosis of smooth muscle cells (SMCs) were studied by implantation of stent into the rabbit’s abdominal aorta for different period. All the animals lived throughout the study. There was no detectable migration or dissection of the stent, and there were no acute closures or sub-acute thromboses in the vessels. The rates of patency were 100% both at the beginning when the stent was implanted and at the end when the animal was sacrificed. It may be concluded that the vascular intima covers the whole stent at the 8-week point. The atherosclerotic process existed in the vascular intima in contact with the stent surface, while the proliferation and apoptosis of SMCs occured simultaneously. After stent implantation, the apoptosis happened in both intima and media, which indicated that the stent might not only stimulate the intima but also compress the media, leading to proliferation and apoptosis. This might contribute to vessel remodeling after stenting.

The pro-oxidant role of methylglyoxal in mesenteric artery smooth muscle cells

2005 ◽  
Vol 83 (1) ◽  
pp. 63-68 ◽  
Author(s):  
Lingyun Wu
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Mesenteric Artery ◽  
Advanced Glycation Endproducts ◽  
Muscle Cells ◽  
Heme Oxygenase 1 ◽  
Rat Mesenteric Artery ◽  
Cultured Smooth Muscle Cells

Methylglyoxal (MG), a highly reactive metabolite of glucose, causes non-enzymatic glycation of proteins to form irreversible advanced glycation endproducts (AGEs). The present study investigated whether methylglyoxal induced oxidative stress and activated nuclear factor kappa B (NF-κB) in freshly isolated and cultured smooth muscle cells (SMCs) from rat mesenteric artery. The treatment of cells with MG (50 or 100 µmol/L) induced a significant increase in AGE formation and oxidation of DCF. MG-enhanced generation of AGEs and the oxidation of DCF was markedly inhibited by antioxidant n-acetylcysteine (NAC, 600 µmol/L). MG at a concentration of 100 µmol/L increased the heme-oxygenase-1 expression in these cells. Moreover, MG activated NF-κB p65, indicated by an increased im muno cytochemistry stain for NF-κB p65 located in the nucleus after the treatment of mesenteric artery SMCs with MG. MG-induced activation of NF-κB p65 was inhibited by NAC. In summary, MG significantly increases oxidative stress and activates NF-κB p65 in mesenteric artery SMCs. The pro-oxidant role of methylglyoxal may contribute to various pathological changes of SMCs from resistance arteries.Key words: methylglyoxal, oxidative stress, NF-κB p65, vascular smooth muscle cells, mesenteric artery.

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