NF- B Activation and Fas Ligand Overexpression in Blood and Plaques of Patients With Carotid Atherosclerosis: Potential Implication in Plaque Instability (original) (raw)
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Stroke, 2004
Background and Purpose— Apoptosis is present in human atherosclerotic lesions. Nuclear factor-κB (NF-κB) is involved in the transcriptional regulation of the proapoptotic protein Fas ligand (FasL). We have analyzed NF-κB activation and FasL expression in atherosclerotic plaques and peripheral blood mononuclear cells (PBMCs) of patients with carotid stenosis. Methods— NF-κB activation and FasL and active caspase-3 expression were analyzed in 32 human carotid plaques. NF-κB activation and FasL mRNA were tested in PBMCs of patients and healthy volunteers. We analyzed whether the NF-κB inhibitor parthenolide regulates FasL expression and cytotoxicity in human T cells. Results— The inflammatory region of plaques showed an increase in NF-κB activation (3393±281 versus 1029±100 positive nuclei per mm 2 , P <0.001) and FasL (16±1.4% versus 13±1.8%, P <0.05) and active caspase-3 (3.3±0.6 versus 1.5±0.3%, P <0.05) expression compared with the fibrous area. Activated NF-κB and FasL pr...
Parthenolide Modulates the NF- B-Mediated Inflammatory Responses in Experimental Atherosclerosis
Arteriosclerosis, Thrombosis, and Vascular Biology, 2006
Objective-Activation of transcription factor NF-B is an important step in the development of vascular damage, because it controls inducible genes, including many inflammatory mediators. The pharmacological modulation of this process is the main objective in the design of new therapies for atherosclerosis. In this work we analyzed the effects of the natural compound parthenolide (PTN), an NF-B inhibitor. Methods and Results-In vascular smooth muscle cells (VSMCs) and monocytes stimulated with lipopolysaccharide (LPS), nontoxic doses of PTN reduced IB␣ degradation, NF-B activation, and MCP-1 expression, without inhibiting AP-1 and MAPK. In apoE mice, treatment with low (2 mg/kg, 20 weeks), medium (4 mg/kg, 10 weeks), and high (10 mg/kg, 10 weeks) dose of PTN reduced the size of aortic lesion, decreased macrophage, and increased VSMC content in the lesions. Treated mice showed reduced serum levels of MCP-1 and attenuated NF-B activity, but not AP-1, in the lesions. Moreover, PTN affects neither apoptotic cell death nor oxidative stress in cultured cells and mice. Conclusion-NF-B inhibition by PTN retards atherosclerotic lesions in apoE mice, by reducing lesion size and changing plaque composition. This natural compound could represent a novel therapeutic approach to inflammation during vascular damage.
Atherosclerosis, 2006
Background and objective: Prostaglandin E 2 (PGE 2 ), a product of the cyclooxygenase 2 (COX-2) and membrane-associated Prostaglandin E Synthase (mPGES-1) pathway, has been implicated in the instability of atherosclerotic plaques. We have studied COX-2, mPGES-1 and PGE 2 receptors (EPs) expression in peripheral blood mononuclear cells (PBMC) and atherosclerotic plaques of 29 patients with carotid stenosis as well as the effect of different nuclear factor-kappaB (NF-B) inhibitors on COX-2, mPGES-1 and EPs expression in cultured monocytic cells (THP-1). Methods: COX-2, mPGES-1 and EP expression was analyzed by RT-PCR (PBMC), immunohistochemistry (plaques) and Western blot (THP-1). PGE 2 levels were determined by ELISA (plasma and cell supernatants). Results: In relation to healthy controls, COX-2, mPGES-1 and EP-3/EP-4 mRNA expression was increased in PBMC from patients. In the inflammatory region of atherosclerotic plaques, an increase of COX-2, mPGES-1 and EPs expression was also observed. Activated NF-B and COX-2, mPGES-1 and EPs proteins were colocalized in the plaque's cells. In cytokine-treated cultured THP-1, the NF-B inhibitors parthenolide, Bay 11-7082 and PDTC reduced COX-2, mPGES-1 and EP-1/EP-3/EP-4 expression as well as PGE 2 levels. By employing specific agonists and antagonists, we noted that the cytokine-and PGE 2 -induced metalloproteinase 9 (MMP-9) expression and activity occurs through EP-1/EP-3/EP-4, an effect downregulated by NF-B inhibitors. Conclusions: Patients with carotid atherosclerosis depict an overexpression of COX-2, mPGES-1 and EPs simultaneously in the PBMC as well as in the vulnerable region of plaques. The studies in cultured monocytic cells suggest that NF-B inhibitors and/or EPs antagonists could represent a novel therapeutic approach to the treatment of plaque instability and rupture. (J. Egido). in inflammatory processes. PGE 2 exerts its effects through specific G protein-coupled cell surface receptors named EPs. EP-1 mediates Ca 2+ mobilization and induces contraction of vascular smooth muscle cells (SMCs). EP-2 and EP-4 cause an increment of intracellular cAMP concentration and induce SMCs relaxation. EP-3 reduces cAMP concentration and inhibits SMCs relaxation . The existence of several PGE 2 receptors
Journal of Cellular and Molecular Medicine, 2010
Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and nitric oxide induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analysed for bFGF, FGF-receptors-1 and -2 (FGFR-1/-2), inducible nitric oxide synthase (iNOS) and MMP-9 expression. Our data revealed increased expression of bFGF and FGFR-1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP-9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up-regulation of both iNOS and MMP-9 that was specifically mediated by nuclear factor-B (NF-B) activation. Collectively, our data demonstrate a novel NF-B-mediated pathway linking bFGF with iNOS and MMP-9 expression that is associated with carotid plaque vulnerability.
Parthenolide Modulates the NF-κB–Mediated Inflammatory Responses in Experimental Atherosclerosis
Arteriosclerosis, Thrombosis, and Vascular Biology, 2006
Objective— Activation of transcription factor NF-κB is an important step in the development of vascular damage, because it controls inducible genes, including many inflammatory mediators. The pharmacological modulation of this process is the main objective in the design of new therapies for atherosclerosis. In this work we analyzed the effects of the natural compound parthenolide (PTN), an NF-κB inhibitor. Methods and Results— In vascular smooth muscle cells (VSMCs) and monocytes stimulated with lipopolysaccharide (LPS), nontoxic doses of PTN reduced IκBα degradation, NF-κB activation, and MCP-1 expression, without inhibiting AP-1 and MAPK. In apoE mice, treatment with low (2 mg/kg, 20 weeks), medium (4 mg/kg, 10 weeks), and high (10 mg/kg, 10 weeks) dose of PTN reduced the size of aortic lesion, decreased macrophage, and increased VSMC content in the lesions. Treated mice showed reduced serum levels of MCP-1 and attenuated NF-κB activity, but not AP-1, in the lesions. Moreover, PTN...
Altered expression of inflammation-related genes in human carotid atherosclerotic plaques
Atherosclerosis, 2012
Objective: Inflammation is a pivotal process in atherosclerosis development and progression, but the underlying molecular mechanisms remain largely obscure. We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis. Methods: We studied 11 human carotid plaques, their respective adjacent regions and 7 control arteries from different subjects. Expression of 92 genes was studied by TaqMan low-density array human inflammation panel. Human aortic endothelial and smooth muscle cells were used for in vitro experiments. Results: The mRNA levels of 44/92 genes (48%) differed significantly between the tissues examined (13 up-regulated and 31 down-regulated). Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway. The expression of PTGIS and PTGIR genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and TNF-␣. Conclusions: This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development. The decrease of PTGIS and PTGIR expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries, which suggests that oxidation is important for PTGIS and PTGIR regulation in human vessel cells during atherosclerosis development.