Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis

Cai, Qiangjun; Lanting, Linda; Natarajan, Rama

doi:10.1152/ajpcell.00170.2004

Cited by 54 publications

(47 citation statements)

References 41 publications

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“…Activation of VSMCs plays an important role in the development of atherosclerosis. Furthermore, because monocyte to macrophage transitions take place in the subendothelial space, VSMCs and monocyte/macrophages may cooperate to augment diabetic vascular dysfunction (26,44). Hence, we next examined inflammatory gene expression in aortic VSMCs isolated from db/ϩ and db/db mice.…”

Section: Resultsmentioning

confidence: 99%

“…We next examined whether the increased inflammatory chemokine gene expression observed in the db/db MVSMCs can lead to enhanced adhesion of monocytes because evidence shows that heterotypic interactions between these cell types may enhance monocyte to macrophage differentiation (44). Adhesion assays with WEHI mouse monocytes and MVSMCs were carried out as described earlier (26,44) and in RESEARCH DESIGN AND METHODS. Results shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the hypertrophic and matrix-inducing effects of angiotensin II and chemotactic migratory effects of platelet-derived growth factor (PDGF) were significantly enhanced in VSMCs cultured under high-glucose conditions (23,25). Interestingly, these growth factors also induced the binding of monocytes to VSMCs, suggesting a novel mechanism for subendothelial monocyte retention in the pathology of atherosclerosis (26). These studies suggest that the diabetic milieu modulates signaling responses in both monocytes and VSMCs, leading to aberrant inflammatory gene expression and pathophysiological responses.…”

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confidence: 99%

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Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

et al. 2006

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Diabetes is associated with enhanced inflammatory responses and cardiovascular complications such as atherosclerosis. However, it is unclear whether similar responses are present in cells derived from experimental animal models of diabetes. We examined our hypothesis that macrophages and short-term cultured vascular smooth muscle cells (VSMCs) derived from obese, insulin-resistant, and diabetic db/db mice would exhibit increased proatherogenic responses relative to those from control db/؉ mice. We observed that macrophages from db/db mice exhibit significantly increased expression of key inflammatory cytokines and chemokines as well as arachidonic acid-metabolizing enzymes cyclooxygenase-2 and 12/15-lipoxygenase that generate inflammatory lipids. Furthermore, VSMCs derived from db/db mice also showed similar enhanced expression of inflammatory genes. Expression of inflammatory genes was also significantly increased in aortas derived from db/db mice. Both macrophages and VSMCs from db/db mice demonstrated significantly increased oxidant stress, activation of key signaling kinases, and transcription factors cAMP response element-binding protein and nuclear factor-B, involved in the regulation of atherogenic and inflammatory genes. Interestingly, VSMCs from db/db mice displayed enhanced migration as well as adhesion to WEHI mouse monocytes relative to db/؉. Thus, the diabetic milieu and a potential hyperglycemic memory can induce aberrant behavior of vascular cells. These new results demonstrate that monocyte/macrophages and VSMCs derived from db/db mice display a "preactivated" and proinflammatory phenotype associated with the pathogenesis of diabetic vascular dysfunction and atherosclerosis. Diabetes

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

et al. 2006

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“…Because adhesive interactions between monocytes and SMCs can contribute to subendothelial monocyte-macrophage retention in atherosclerosis, 20,21 we initially examined whether inhibiting FGFR signaling would affect expression of hyaluronan synthase. Hyaluronan synthase can be induced by fibroblast growth factor 22 and when overexpressed in SMCs increases monocyte binding 21,23 ; also overexpression of hyaluronan, the product of hyaluronan synthase (HAS), promotes atherosclerosis.…”

Section: Factors Affecting Monocyte Retentionmentioning

confidence: 99%

“…Similarly, the level of the oxLDL receptor CD36 mRNA, the expression of which is known to increase when monocytes interact with SMCs, 24 was reduced by Ϸ90%. Strikingly, cyclooxygenase-2 (COX-2), the expression of which also enhances SMCmonocyte interactions 20 and which can be induced by FGF-2 in SMCs, 24 was almost completely abolished by treatment with SU5402. Finally, endothelial monocyte-activating polypeptide-II (EMAP-II), which can also promote binding of monocytes to SMCs, 25 was also reduced in expression after inhibition of FGFR signaling, although to a lesser extent (Ϸ45%) than the other retention factors.…”

Section: Factors Affecting Monocyte Retentionmentioning

confidence: 99%

Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice

Raj

Kanellakis

Pomilio

et al. 2006

ATVB

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Objective-To determine the significance of fibroblast growth factor receptor (FGFR) expression for the development of atherosclerotic lesions in apoE-deficient (apoE Ϫ/Ϫ ) mice. Methods and Results-ApoEϪ/Ϫ mice fed a high-fat diet were administered the FGFR tyrosine kinase inhibitor SU5402 (25 mg/kg/d sc), which inhibited neointima growth by 85%. We measured its effects on lesion size at the aortic sinus, macrophage and smooth muscle cell (SMC) accumulation, the expression of monocyte chemotactic and retention factors, as well as its effects on FGFR expression/phosphorylation. FGFR tyrosine kinase inhibition reduced phosphorylated FGFRs in lesions by 90%, associated with a 65% reduction in lesion size measured using Oil Red O. Macrophages and SMCs within lesions were reduced by 58% and 78%, respectively. Monocyte chemotactic protein-1 (MCP-1) expression was also reduced, as was the expression of hyaluronan synthase, cyclooxygenase-2, CD36, and endothelial monocyte-activating polypeptide-II. Although 3 FGFR types were expressed in lesions, the effects of SU5402 could be attributed largely to inhibition of FGFR-1 phosphorylation. Conclusions-Atherosclerotic lesions in apoEϪ/Ϫ mice express multiple FGFRs and an active FGF:FGFR-1 signaling system that promotes atherosclerosis development via increased SMC proliferation, and by augmenting macrophage accumulation via increased expression of MCP-1 and factors promoting macrophage retention in lesions.

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LDL induces Saos2 osteoblasts death via Akt pathways responsive to a neutral sphingomyelinase inhibitor

Klein

Kerem

Rojansky

2006

J of Cellular Biochemistry

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Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis (OP) presumably by common etiologic factors, reflecting a state of co-morbidity in aging. Osteoblasts make a significant facet of this co-morbidity state. Since oxidized low-density lipoprotein (oxLDL) is a major factor in generation of vascular wall pathology, we examined the ability of native LDL (nLDL) and oxLDL to induce Saos2 osteoblasts growth arrest. OxLDL induced Saos2 cell death with morphological features of apoptosis that was inhibited mainly by caspase-9 and partially by caspase-3 but not by caspase-8 inhibitors. nLDL, like oxLDL, has induced cell death, where 60% (P = 0.00033) and 30% (P = 0.075, ns) of the cell death, respectively, could be inhibited by scyphostatin (a neutral sphingomyelinase [nSMase] inhibitor). Upon similar condition, nLDL inhibited the phosphorylation of Akt and two of its downstream targets, fork head receptor (FKHR) and glycogen synthase kinase-3 (GSK3). This is a pathway that stimulates cell survival and proliferation. nLDL has also induced an increase in the proapoptotic Bcl-Xs and it has diminished the potential antiapoptotic Src kinase activity. At the 4 h time-point, upon a substantial decrease in nLDL-induced Akt phosphorylation, scyphostatin has inhibited the reduction in FKHR and GSK3 phosphorylation but inexplicably not that of Akt. Scyphostatin has also corrected the reduction in Src kinase activity. Taken together, the results indicate that nLDL has induced apoptosis in Saos2 osteoblasts by inactivation of the pathway downstream to Akt using nSMase, and by involvement of Src kinase. Inferring that caspase-9 was the main executioner (rather than caspase-8 and-3) in Saos2 cell death, indicates that the nSMase-induced release of ceramide, directly activated the intrinsic mitochondrial apoptotic pathway. With regard to the Akt inactivation by nLDL, Saos2 osteoblasts responded in an opposite fashion to the response reported by others, in macrophages.

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Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis

Cited by 54 publications

References 41 publications

Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice

LDL induces Saos2 osteoblasts death via Akt pathways responsive to a neutral sphingomyelinase inhibitor

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