Inflammation meets oxidation: NF-κB as a mediator of initial lesion development in atherosclerosis

Kütük, Özgür; Başağa, Hüveyda

doi:10.1016/j.molmed.2003.10.007

Cited by 130 publications

(81 citation statements)

References 91 publications

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“…71 Inflammation has been shown to play a major role in atherogenesis, 72 particularly through nuclear factor B (NF-B) activation. 73 Interestingly, ROR␣ exerts antiinflammatory activities through inhibition of the NF-B signaling pathway (this aspect is described under "Inflammation"). It is therefore likely that the enhanced atherosclerotic susceptibility of Rora sg/sg mice is related both to low HDL plasma levels and to exaggerated inflammatory response to the high-fat, high-cholesterol diet.…”

Section: Ror␣ Lipid Metabolism and Atherosclerosismentioning

confidence: 99%

The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

ATVB

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Abstract-Retinoic acid receptor-related Orphan Receptor ␣ (ROR␣) is a member of the nuclear hormone receptor superfamily. ROR␣ has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of ROR␣. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of ROR␣ activity. The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, ROR␣ appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making ROR␣ an intracellular cholesterol target. Key Words: ROR␣ Ⅲ cholesterol Ⅲ statins Ⅲ atherosclerosis Ⅲ lipid homeostasis R etinoic acid receptor-related Orphan Receptor ␣ (ROR␣), initially described as an orphan nuclear receptor, has recently been deorphanized by the identification of its natural ligand as cholesterol or a cholesterol derivative. 1,2 ROR␣ has been shown to be implicated in the development and/or differentiation of many tissues, and provides protection against age-related degenerative processes, including atherosclerosis. In addition, ROR␣ activates the apolipoprotein A-I (apoA-I) and apoC-III gene transcription, 3,4 modulates the vasomotor tone of small resistance arteries, and participates in the regulation of postischemic angiogenesis. 5,6 This review focuses on the link between ROR␣, vascular biology, and cholesterol homeostasis. Interestingly, recent findings suggest that ROR␣ is an intracellular cholesterol target. 1

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Section: Ror␣ Lipid Metabolism and Atherosclerosismentioning

confidence: 99%

The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

ATVB

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“…Oxidative modification of low-density lipoprotein (LDL) and ''vascular inflammatory process'' are the two fundamental mechanisms, recognized widely to be involved in atherogenesis. In fact, cooperativity between oxidation and inflammation seems to be the key event in the development of early atherosclerotic lesions [2].…”

Section: Introductionmentioning

confidence: 99%

Importance of blood cellular genomic profile in coronary heart disease

2005

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SummarySince receptor/transcription factor family especially peroxisome proliferator-activated receptors PPARs (a, c) and liver X receptor a (LXRa) have been recognized to play crucial role in both lipid metabolism and inflammation, the present study was addressed to explore the interrelationship between blood cellular genomic expression profile, serum lipid levels and severity of coronary heart disease (CHD) in human subjects. Based upon the demographic and laboratory data, the human subjects were divided into 4 groups. Genomic expression profile in the subjects belonging to these groups was determined by measuring the transcriptional expression of genes coding for PPARs (a, c), CD36, LXRa and low density lipoprotein receptor (LDLR) in their blood mononuclear cells. This genomic expression profile was correlated with serum lipid profile as well as with the severity of CHD (revealed by coronary angiography coupled with modified Gensini score) using standard statistical analytical methods. Further in vitro and in vivo effect of statins on such genomic profile was also explored. Although genes coding for PPARs (a, c), CD36, LDLR showed correlation with the severity of coronary atherosclerosis , blood cellular LXRa genomic profile showed conspicuous negative correlation with the severity of coronary atherosclerosis in subjects with or without hypercholesterolemia. This view was further confirmed in experiments directed to understand the effect of statins on the cellular genomic profile of PPARs (a, c) and LXRa. Based on these reported findings, we propose that blood cellular LXRa genomic profile has a protective effect against the development of CHD and hence may be of importance in devising synthetic therapeutic drugs for CHD in future.

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“…Cooperativity between lipid peroxidation and inflammation has been widely recognized to initiate a complex interaction between blood mononuclear cells (neutrophils, lymphocytes and monocytes) and cells within vascular wall leading to atherogenic process (Kutuk & Basaga, 2003). The first stage at which these two pathological processes intersect seems to be the regulation of nuclear receptor/transcription factor family involving peroxisome proliferator-activated receptors (PPARs a, g) and liver X receptor-a (LXR-a) in a manner that gives rise to the development of early lesions.…”

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confidence: 99%

Genomic effect of vitamin ‘C’ and statins within human mononuclear cells involved in atherogenic process

Kaul

Baba

2005

Eur J Clin Nutr

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Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-a (LXR-a), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (a, g) genes and upregulate LXR-a gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-a gene expression was in conformity with the downregulatory effect of LXR-a on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-a-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

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Inflammation meets oxidation: NF-κB as a mediator of initial lesion development in atherosclerosis

Cited by 130 publications

References 91 publications

The “CholesteROR” Protective Pathway in the Vascular System

The “CholesteROR” Protective Pathway in the Vascular System

Importance of blood cellular genomic profile in coronary heart disease

Genomic effect of vitamin ‘C’ and statins within human mononuclear cells involved in atherogenic process

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