Carbon Monoxide Suppresses Neointima Formation in Transplant Arteriosclerosis by Inhibiting Vascular Progenitor Cell Differentiation

2021 ◽  
Author(s):  
Hideyasu Sakihama ◽  
Ghee Rye Lee ◽  
Beek Y. Chin ◽  
Eva Csizmadia ◽  
David Gallo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Carbon Monoxide ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Bone Marrow Cell ◽  
Marrow Cell ◽  
Neointima Formation ◽  
Transplant Arteriosclerosis

Objective: Evidence indicates that bone marrow progenitor cells (BMPC) are a major contributor to neointima formation in transplant arteriosclerosis. HO-1 (heme oxygenase 1, Hmox1 ) and carbon monoxide (CO), a product of heme degradation by HO-1, ameliorate neointima formation by inhibiting proliferation of smooth muscle cells. We investigated the mechanism whereby HO-1 and CO modulate BMPC and mitigates neointima formation in transplant arteriosclerosis. Approach and Results: Using a murine model of aortic transplantation, bone marrow chimeric mice, and in vitro experiments, we report that CO does not inhibit mobilization of BMPC into the circulation or their homing to the vessel adventitia, but instead suppresses differentiation of BMPC into smooth muscle cells after they arrive in the adventitia. Specifically, the effect of CO on differentiation of BMPC into smooth muscle cell is mediated in part, by limiting PDGFR-β (platelet derived growth factor receptor-β) signaling. Hmox1 −/− BMPC exhibit a greater propensity to differentiate into smooth muscle cell in vitro, in part by regulating PDGFR-β + expression. Furthermore, wild-type mice transplanted with Hmox1 −/− bone marrow cells show augmented neointima formation after allografting versus control. CO exposure significantly ameliorated neointima formation, which remains more severe with Hmox1 −/− bone marrow cell versus air-treated mice receiving HO-1-expressing bone marrow cell, highlighting the importance of endogenous HO-1 in neointima formation. Conclusions: Host BMPC contribute to neointima formation in transplant arteriosclerosis and the protective effect afforded by HO-1/CO against neointima formation is mediated in part through the regulation of PDGFR-β expression. We propose that suppressing differentiation of BMPC is a major mechanism by which HO-1 and CO prevent neointima expansion after transplant.

scholarly journals Cannabinoid receptor CB2 protects against balloon-induced neointima formation

2012 ◽  
Vol 302 (5) ◽  
pp. H1064-H1074 ◽  
Author(s):  
Filippo Molica ◽  
Christian M. Matter ◽  
Fabienne Burger ◽  
Graziano Pelli ◽  
Sébastien Lenglet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cannabinoid Receptor ◽  
Muscle Cells ◽  
Mrna Levels ◽  
Neointima Formation ◽  
Balloon Injury ◽  
And Migration

Cannabinoid receptor CB2 activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE−/−) mice receiving daily intraperitoneal injection of the CB2 agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB2−/− and wild-type (WT) mice to balloon injury. We determined CB2 mRNA and protein expression in dilated arteries of ApoE−/− mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB2−/− and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB2 expression in ApoE−/− mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB2 deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB2−/− mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB2 knockouts. In vitro, bone marrow-derived CB2−/− macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB2−/− smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB2 receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells.

scholarly journals Time-Course Analysis on the Differentiation of Bone Marrow-Derived Progenitor Cells Into Smooth Muscle Cells During Neointima Formation

2010 ◽  
Vol 30 (10) ◽  
pp. 1890-1896 ◽  
Author(s):  
Jan-Marcus Daniel ◽  
Wiebke Bielenberg ◽  
Philipp Stieger ◽  
Soenke Weinert ◽  
Harald Tillmanns ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Progenitor Cells ◽  
Time Course ◽  
Muscle Cells ◽  
Neointima Formation

scholarly journals INCORPORATION IN VITRO OF LABELED AMINO ACIDS INTO BONE MARROW CELL PROTEINS

1950 ◽  
Vol 186 (1) ◽  
pp. 297-307 ◽  
Author(s):  
Henry. Borsook ◽  
Clara L. Deasy ◽  
A.J. Haagen-Smit ◽  
Geoffrey. Keighley ◽  
Peter H. Lowy
Keyword(s):  
Amino Acids ◽  
Bone Marrow ◽  
Bone Marrow Cell ◽  
Marrow Cell

Abstract 102: Cd98 Modulates Atherosclerotic Plaque Morphology by Regulating Smooth Muscle Cell Proliferation via the P-38 Map Kinase Pathway

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Sara McCurdy ◽  
Yvonne Baumer ◽  
Franz Hess ◽  
William A Boisvert
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Atherosclerotic Plaque ◽  
Necrotic Core ◽  
Plaque Morphology ◽  
Fibrous Cap ◽  
Plaque Area

Smooth muscle cells (SMC) are known to migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. It has been shown that CD98hc, a transmembrane protein with a known role in amino acid transport and integrin signaling, is involved in proliferation and survival of various cell types including SMC. Based on these data, we hypothesized that CD98hc deficiency selectively in SMC would have pathogenic effects on atherosclerosis development and plaque composition. To test this, we utilized mice with SMC-specific deletion of the CD98hc ( CD98hc fl/fl SM22Cre + ) to determine the effects of CD98hc deficiency on SMC function in the context of atherosclerosis. We performed in vitro proliferation and survival/apoptosis assays to investigate the role of CD98hc in the proliferation and survival of primary mouse aortic vascular smooth muscle cells. We found that VSMC isolated from whole aortas of CD98hc -/- animals displayed approximately 60% reduced cell counts compared to control (41 ± 8.2% of control) after 5 days in culture. EdU assays in vivo showed a defect in the ability of CD98hc -/- SMC to proliferate, with 25% reduction in EdU-positive VSMC compared to controls (2.3 ± 0.2% vs 3 ± 0.2%). In addition, caspase-3 staining of SMC in vitro displayed a 41% increase in propensity of CD98hc -/- SMC to undergo apoptosis compared to controls (7.9 ± 0.6% vs 5.6 ± 0.5%). Furthermore, the absence of CD98hc in SMC caused a sharp increase in phosphorylated p-38, which was partially abrogated towards control levels when the cells were treated with PDGF-BB to induce proliferation. Long-term atherosclerosis study using SMC-CD98hc -/- /LDLR -/- mice showed that atherosclerotic plaque morphology was altered with increased necrotic core area (25.8 ± 1.9% vs 10.9 ± 1.6% necrotic core area per plaque area) due to a reduction in infiltration of SMC within the plaque (2.1 ± 0.4% vs 4.3 ± 0.4% SM22α positive area per plaque area) compared to control LDLR -/- mice. These data support an important role for CD98hc and its regulation of p-38 MAP kinase signaling in aortic vascular smooth muscle cell proliferation and survival. We conclude that CD98hc is critical for the formation of fibrous cap that is important in maintaining the stability of atherosclerotic plaque.

scholarly journals Interleukin-1 (22-K factor) induces release of granulocyte-macrophage colony-stimulating activity from human mononuclear phagocytes

Blood ◽  
1986 ◽  
Vol 68 (6) ◽  
pp. 1316-1321 ◽  
Author(s):  
WE Fibbe ◽  
J van Damme ◽  
A Billiau ◽  
PJ Voogt ◽  
N Duinkerken ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cell ◽  
Marrow Cell ◽  
Interleukin 1 ◽  
Colony Growth ◽  
Cell Suspensions ◽  
Mononuclear Phagocytes ◽  
Adherent Cells ◽  
Macrophage Colony

Abstract An electrophoretically pure preparation of natural human interleukin-1 (IL-1) was shown to stimulate in vitro colony formation in human bone marrow cultures. Day 4 myeloid cluster-forming cells (CFC), as well as early (day 7) and late (day 10) granulocyte-macrophage colony-forming units (CFU-GM) were stimulated in a dose-dependent fashion. At optimal concentrations of IL-1, the number of day 4 CFC reached 72%, the number of day 7 CFU-GM reached 32%, and the number of day 10 CFU-GM reached 80% of the respective numbers of colonies obtained by addition of crude leukocyte-conditioned medium (LCM). The IL-1-induced stimulatory effect on CFU-GM growth could be completely neutralized by a rabbit anti-IL-1 antiserum. Colony growth was abrogated by depleting the marrow cell suspensions of phagocytic cells prior to IL-1 addition. Conversely, the effect could be reintroduced by addition of marrow-derived adherent cells to bone marrow cell suspensions that had been depleted of both phagocytic and E rosetting T cells. Furthermore, media conditioned by bone marrow-derived adherent cells or by peripheral blood mononuclear phagocytes in the presence but not in the absence of IL-1, stimulated in vitro colony growth of phagocyte-depleted bone marrow cell suspensions. These results indicate that IL-1 induces release of granulocyte-macrophage colony-stimulating activity (GM-CSA) from human mononuclear phagocytes.

scholarly journals Brief Report: The Di Guglielmo Syndrome: Studies in Hemoglobin Synthesis

Blood ◽  
1967 ◽  
Vol 29 (4) ◽  
pp. 550-553 ◽  
Author(s):  
THOMAS F. NECHELES ◽  
WILLIAM DAMESHEK
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cell ◽  
Clinical Course ◽  
Marrow Cell ◽  
Cell Suspensions ◽  
In Vitro Synthesis ◽  
Hemoglobin Synthesis ◽  
Heme Synthesis ◽  
Globin Synthesis

Abstract The in vitro synthesis of heme and globin has been studied in bone marrow cell suspensions obtained from five patients with Di Guglielmo syndrome. In all, a defect of heme synthesis was demonstrated, but globin synthesis was greatly reduced in only two of the five; in these two, the clinical course was a rapid one.

Cytokine Requirement For The Growth and Differentiation Of Rat Dendritic Cell (DC) Precursors With In Vitro Bone Marrow Cell Cultures

1999 ◽  
Vol 67 (9) ◽  
pp. S604
Author(s):  
Toko Miyagi ◽  
Xiao-Kang Li ◽  
Masayuki Fujino ◽  
Hirohisa Saito ◽  
Daniel P Gold ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cell ◽  
Bone Marrow Cell ◽  
Cell Cultures ◽  
Marrow Cell

The Effect of a Calf Thymus Acid Lysate on Bone Marrow Cell Growth in Vitro

1988 ◽  
Vol 10 (4) ◽  
pp. 523-536
Author(s):  
G. Vasilopoulos ◽  
A. Porwit ◽  
L. Lauren ◽  
P. Reizenstein ◽  
P. Cazzola
Keyword(s):  
Bone Marrow ◽  
Cell Growth ◽  
Bone Marrow Cell ◽  
Marrow Cell ◽  
Calf Thymus
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