Rapamycin attenuates vascular wall inflammation and progenitor cell promoters after angioplasty

Nührenberg, Thomas; Voisard, Rainer; Fahlisch, Felicitas; Rudelius, Martina; Braun, Jürgen; Gschwend, Jürgen E.; Kountides, Margaratis; Herter, Tina; Baur, Regine; Hombach, Vinzenz; Baeuerle, Patrick A.; Zohlnhöfer, Dietlind

doi:10.1096/fj.04-2431fje

Cited by 53 publications

(36 citation statements)

References 46 publications

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“…Our study suggests that rapamycin interferes with IKK function and, hence, prevents TNF-␣-induced NF-B activation. This notion is supported by the finding that rapamycin exerted an anti-inflammatory effect in a human model of angioplasty (27). Accordingly, we found that induction of the prosurvival Bcl-2 homologs Bcl-X L and Bfl-1/A1, which are transcriptional targets of NF-B (10,46), was inhibited by rapamycin, and, as expected, the extent of apoptosis of VSMCs cultured with rapamycin ϩ TNF-␣ was greater than that of cells cultured with the cytokine alone.…”

Section: Discussionmentioning

confidence: 74%

Rapamycin antagonizes NF-κB nuclear translocation activated by TNF-α in primary vascular smooth muscle cells and enhances apoptosis

Giordano

Avellino²,

Ferraro³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionmentioning

confidence: 74%

Rapamycin antagonizes NF-κB nuclear translocation activated by TNF-α in primary vascular smooth muscle cells and enhances apoptosis

Giordano

Avellino²,

Ferraro³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Numerous publications have described a central role for the SDF-1/CXCR4 axis in new vessel formation, vascular wound repair, and VSMC proliferation (5,48,(59)(60)(61)(62)(63). Zernecke et al (63) found that the transplantation of CXCR4 -/-fetal liver cells into ApoE -/-mice resulted in a greater than 50% reduction in neointimal area after vascular wire injury, suggesting a regulatory role for inflammatory and/or immune cells in wound repair and VSMC proliferation.…”

Section: Discussionmentioning

confidence: 99%

p21Cip1 modulates arterial wound repair through the stromal cell–derived factor-1/CXCR4 axis in mice

Olive¹,

Mellad²,

Beltran³

et al. 2008

J. Clin. Invest.

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Cyclin-dependent kinase inhibitors, including p21 Cip1 , are implicated in cell turnover and are active players in cardiovascular wound repair. Here, we show that p21 Cip1 orchestrates the complex interactions between local vascular and circulating immune cells during vascular wound repair. In response to femoral artery mechanical injury, mice with homozygous deletion of p21 Cip1 displayed accelerated proliferation of VSMCs and increased immune cell infiltration. BM transplantation experiments indicated that local p21 Cip1 plays a pivotal role in restraining excessive proliferation during vascular wound repair. Increased local vascular stromal cell-derived factor-1 (SDF-1) levels were observed after femoral artery injury in p21 +/+ and p21 -/-mice, although this was significantly greater in p21 -/-animals. In addition, disruption of SDF-1/CXCR4 signaling inhibited the proliferative response during vascular remodeling in both p21 +/+ and p21 -/-mice. We provide evidence that the JAK/STAT signaling pathway is an important regulator of vascular SDF-1 levels and that p21 Cip1 inhibits STAT3 binding to the STAT-binding site within the murine SDF-1 promoter. Collectively, these results suggest that p21 Cip1 activity is essential for the regulation of cell proliferation and inflammation after arterial injury in local vascular cells and that the SDF-1/CXCR4 signaling system is a key mediator of vascular proliferation in response to injury.

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“…In both mouse strains, we found genes known to be regulated during neointima formation such as MMP-9, VEGF, and desmin. 15 Whereas the involvement of proliferation and apoptosis of SMCs and the production of extracellular matrix are well known during neointima formation the impact of inflammatory processes leading to leukocyte recruitment as well as the impact of HSPC recruitment after vascular injury have been underlined more recen- …”

Section: The Mechanisms Leading To Lumen Narrowing In the Vascular Rementioning

confidence: 99%

Role of Bone Marrow–Derived Cells in the Genetic Control of Restenosis

Langwieser

Schwarz²,

Reichenbächer³

et al. 2009

ATVB

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Objective-Angiographic indexes of restenosis after coronary stent placement in patients show a bimodal pattern suggesting the existence of two populations with different risk of restenosis. This is reflected in the arterial remodeling response of inbred mouse strains arguing for a genetic control of the mechanisms leading to lumen narrowing. As bone marrow-derived cells (BMCs) contribute to vascular healing after arterial injury, we investigated the role of BMCs in the genetic control of restenosis. Methods and Results-129X1/SvJ mice developed significantly more neointima and late lumen loss compared to C57BL/6 mice. Gene expression analysis of intimal tissue revealed major differences in the expression of inflammatory and hematopoietic stem and progenitor cell-associated genes in response to arterial injury. In 129X1/SvJ mice stronger mobilization of lin Ϫ sca-1 ϩ CXCR4 ϩ cells was observed after vascular injury. Bone marrow transplantation identified the extent of neointima formation as clearly dependent on the genetic background of BMCs (ie, mice with 129X1/SvJ BMCs developed more intimal hyperplasia). The inflammatory response and the recruitment of BMCs to the site of arterial injury were significantly increased in mice with 129X1/SvJ BMCs. 3 This process was formerly considered to be primarily directed by dedifferentiation and proliferation of medial smooth muscle cells (SMCs). 4 Recently, it has been demonstrated that recruitment of inflammatory cells and bone marrow-derived cells (BMCs) is an essential step in the pathogenesis of vascular remodeling. [5][6][7][8][9] In mice, up to 60% of intimal SMCs originate from the bone marrow. 7 In patients, a progenitor cell-associated gene expression pattern such as the induction of the stromal cell-derived factor 1␣ (SDF-1␣) receptor CXCR-4 or the granulocyte-colony stimulating factor (G-CSF) receptor in neointimal SMCs from coronary in-stent restenosis further argues for the impact of the recruitment of circulating hematopoietic stem and progenitor cells (HSPCs) to the site of vascular injury. 9 Likewise, inhibition of SDF-1␣, a key regulator of HSPC mobilization and recruitment, significantly reduces intimal hyperplasia after vascular injury in mice. 8 Conclusions-The See accompanying article on page 1407Angiographic indexes of restenosis after coronary stent placement follow a bimodal pattern, suggesting the existence of 2 populations with different risk of restenosis. 10 This finding is reflected in a wide variation in the arterial remodeling response in various inbred strains of mice after vessel ligation, arguing that the mechanisms leading to lumen narrowing in the vascular remodeling process are genetically controlled. 11 Whereas vessel ligation only leads to flow cessation, arterial injury by insertion of a standard guide wire induces endothelial denudation and dilatation of the vessel wall with injury of the media. As previously reported, wire injury yields substantial intimal hyperplasia in 129X1/SvJ mice, analogous to the situation in patients after ...

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Rapamycin attenuates vascular wall inflammation and progenitor cell promoters after angioplasty

Cited by 53 publications

References 46 publications

Rapamycin antagonizes NF-κB nuclear translocation activated by TNF-α in primary vascular smooth muscle cells and enhances apoptosis

Rapamycin antagonizes NF-κB nuclear translocation activated by TNF-α in primary vascular smooth muscle cells and enhances apoptosis

p21Cip1 modulates arterial wound repair through the stromal cell–derived factor-1/CXCR4 axis in mice

Role of Bone Marrow–Derived Cells in the Genetic Control of Restenosis

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