Bone Marrow–Derived Cells Contribute to Vascular Inflammation but Do Not Differentiate Into Smooth Muscle Cell Lineages

Iwata, Hiroshi; Manabe, Ichiro; Fujiu, Katsuhito; Yamamoto, Takayoshi; Takeda, Norifumi; Eguchi, Kosei; Furuya, Akiko; Kuro‐o, Makoto; Sata, Masataka; Nagai, Ryozo

doi:10.1161/circulationaha.110.965202

Cited by 115 publications

(109 citation statements)

References 27 publications

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“…Although the majority of VSMCs reside in the tunica media, some VSMCs or VSMC-like cells are also present in the tunica intima and/or can be recruited to the intima in response to vascular injury (Shanahan and Weissberg 1998;Owens et al 2004;Fukuda and Aikawa 2010;Iwata et al 2010). The tunica intima, which is generally much thicker in human arteries compared with other mammals, does not contain elastic fibers.…”

Section: Structure Of the Arterial Vessel Wallmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Structure Of the Arterial Vessel Wallmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…Previous reports have suggested that there are fewer inflammatory cells in the neointima, 32) and that bone marrow-derived cells in the neointima lesion mainly differentiate into macrophage lineages. 33) Thus, the main role of these cells in the development of a neointimal lesion is to initiate inflammation and induce VSMC proliferation. Kosuge, et al indicated that activated T cells induced VSMC proliferation, which might contribute to neointimal formation of arteriosclerosis.…”

Section: Discussionmentioning

confidence: 99%

A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

et al. 2012

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SummaryRestenosis after percutaneous coronary intervention (PCI) is still a clinically serious problem. We examined the treatment efficacy of IMD-0354, a novel IKK inhibitor, on arteriopathy. Using C57BL/6J mice, a wire-injury model was prepared and the mice were intraperitoneally injected with IMD-0354 or vehicle twice a day. The vehicle-treated injured arteries showed significantly thickened intima (3.77 ± 0.59, n = 8), however, IMD-0354 suppressed its progression (1.62 ± 0.22, n = 10, P < 0.05) on day 28. While enhanced expression of PCNA and NF-κB was observed in the untreated injured arteries, IMD-0354 significantly suppressed their expressions. Quantitative RT-PCR revealed that the expression of several inflammatory factors was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases. (Int Heart J 2012; 53: 133-138) Key words: IKK inhibitor, Chemical compound, Arterial remodeling, Inflammation, Smooth muscle R estenosis, which consists of neointimal formation after percutaneous coronary intervention (PCI), is a clinically serious problem. 1-3) Because inflammation is an essential pathological feature of neointimal formation, nuclear factor-kappa B (NF-κB) plays an important role in this process. 4) In humans, activated NF-κB is detected in restenotic lesions.5) Thus, NF-κB regulation has the potential to suppress its progression.Activation of NF-κB induces gene expression that leads to transactivation of adhesion molecules, cytokines and chemokines, promoting the inflammatory status involved in arterial injury. NF-κB is a dimer of the Rel family members and the most common active form is composed of p50 or p52 and p65. In resting cells, NF-κB is inactive and segregated in the cytoplasm, and bound to an inhibitory protein known as the inhibitor of NF-κB (IκB). NF-κB activation requires phosphorylation of IκB by IκB kinase (IKK) complex. The phosphorylated IκB is then ubiquitinated and degraded by proteasomes. Subsequently, the unbound NF-κB is translocated to the nucleus and binds to the promoter or enhancer of specific genes, including those involved in inflammatory reactions. 6)Recently, the first clinical use of an NF-κB decoy oligonucleotide at the site of coronary stenting for the prevention of restenosis was reported. 7,8) However, the indispensable role played by NF-κB in many biological processes has raised the concern that a complete shutdown of this pathway would have significant detrimental effects on normal cellular function. Instead, drugs that selectively target only inflammation-induced NF-κB activity would be of greater therapeutic value. IMD-0354, a novel NF-κB inhibitor, is a drug that specifically suppresses IKK-β activity.9) In this study, we investigated the effects of IMD-0354 on neointimal formation in vivo and VSMC proliferation in vitro. MethodsArterial injury models in mice: Male mice (C57BL/6, age 6-8 weeks, 20-25 g; Japa...

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“…Our in vitro experiment showed that IL-6 accelerates the differentiation of bone marrow cells into alpha actin-positive cells. Iwata et al 21) indicated that bone marrow-derived cells are unlikely to form a definitive smooth muscle cell lineage, instead inducing monocyte/macrophage lineages. Our immunohistological findings also indicated that the neointimal portion after injury does not show positive staining for definitive smooth muscle cell lineage markers (data not shown) as Iwata et al described.…”

Section: Il-6 Bmtmentioning

confidence: 99%