Early Involvement of ROS Overproduction in Apoptosis Induced by 7-Ketocholesterol

Leonarduzzi, Gabriella; Vizio, Barbara; Sottero, Barbara; Verde, Veronica; Gamba, Paola; Mascia, Cinzia; Chiarpotto, Elena; Poli, Giuseppe; Biasi, Fiorella

doi:10.1089/ars.2006.8.375

Cited by 71 publications

(48 citation statements)

References 19 publications

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“…Among the bioactive lipids in oxLDL, oxysterols have been shown to be involved at all stages of atherosclerosis development, and they play an important role in plaque formation ( 24,25 ). In the early stage of atherosclerosis, oxysterols are involved in impairment of several endothelial functions, such as endothelial nitric-oxide synthase (eNOS) activation ( 26 ), reactive oxygen species (ROS) production ( 27 ), and regulation of the permeability barrier ( 28,29 ). In the late stage of atherosclerosis, an increase in the levels of oxysterols was shown to contribute to apoptosis of vascular cells ( 29,30 ) and degradation of extracellular matrix ( 31,32 ), which led to instability of the plaque.…”

Section: Afm Microindentationmentioning

confidence: 99%

The role of oxysterols in control of endothelial stiffness

Shentu

Singh

et al. 2012

Journal of Lipid Research

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Multiple studies have shown that oxidative modifi cations of LDL (oxLDL) are a major factor in the development of atherosclerosis ( 1-6 ). The level of oxLDL increases dramatically with hypercholesterolemia in animal models of atherosclerosis ( 7,8 ), and in humans ( 9, 10 ), it is found in atherosclerotic lesions ( 11 ). It is also well established that dyslipidemia-induced dysfunction of vascular endothelial cells is a critical step in the early stage of atherosclerosis (e.g., Refs. 12-14 ) and a strong predictor of cardiovascular disease (CVD) development ( 15-17 ). The mechanisms, however, of dyslipidemia-induced endothelial dysfunction are still poorly understood. Our recent studies have shown that exposure to oxLDL in vitro or to plasma dyslipidemia in vivo signifi cantly increases the stiffness of aortic endothelial cells, which in turn is associated with an increase in endothelial contractility, enhanced angiogenic potential, and sensitivity to shear stress (18)(19)(20). Furthermore, unexpectedly, our studies showed that dyslipidemia-induced endothelial stiffening is caused not by cholesterol loading but by disruption of lipid packing of cholesterol-rich membrane domains in endothelial cells ( 18,19,21 ). Consistent with these observations, oxLDLinduced endothelial stiffness could be fully reversed by enriching the cells with cholesterol, even though oxLDL had no effect on the cholesterol content of endothelial membranes ( 19 ). These studies led us to the hypothesis that oxLDL induces endothelial dysfunction by inserting oxysterols into the plasma membrane, resulting in the disruption of cholesterol-rich membrane domains and endothelial stiffening. The goal of this study, therefore, was to determine the impact of oxysterols on endothelial stiffness.Abstract Endothelial dysfunction is a key step in atherosclerosis development. Our recent studies suggested that oxLDL-induced increase in endothelial stiffness plays a major role in dyslipidemia-induced endothelial dysfunction. In this study, we identify oxysterols, as the major component of oxLDL, responsible for the increase in endothelial stiffness. Using Atomic Force Microscopy to measure endothelial elastic modulus, we show that endothelial stiffness increases with progressive oxidation of LDL and that the two lipid fractions that contribute to endothelial stiffening are oxysterols and oxidized phosphatidylcholines, with oxysterols having the dominant effect. Furthermore, endothelial elastic modulus increases as a linear function of oxysterol content of oxLDL. Specifi c oxysterols, however, have differential effects on endothelial stiffness with 7-ketocholesterol and 7 ␣ -hydroxycholesterol, the two major oxysterols in oxLDL, having the strongest effects. 27-hydroxycholesterol, found in atherosclerotic lesions, also induces endothelial stiffening. For all oxysterols, endothelial stiffening is reversible by enriching the cells with cholesterol. ox-LDL-induced stiffening is accompanied by incorporation of oxysterols into endothelial cells. We fi nd signif...

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Section: Afm Microindentationmentioning

confidence: 99%

The role of oxysterols in control of endothelial stiffness

Shentu

Singh

et al. 2012

Journal of Lipid Research

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“…412 Besides cholesterol, its active metabolite, 7-ketocholesterol, induced ROS-mediated apoptosis of murine macrophage, and this was inhibited by metabolic inhibitors of NADPH-oxidase and the antioxidant epicatechin. 413 The alanine allele in the signal peptide of MnSOD increases its mitochondrial activity and protects macrophages against the Ox-LDL-induced apoptosis, thereby reducing the risk of coronary artery disease (CAD). 414 Cell surface expression analysis by flow cytometry and confocal microscopy revealed that Ox-LDL increased ceramide and lactosylceramide expression compared to enzymatically degraded low-density lipoprotein (E-LDL) loading and induced ceramide rafts, whereas loading with E-LDL induced cholesterol-rich micro domains.…”

Section: M a C R O P H A G E A P O P T O S I S A N D P H A G O C Y mentioning

confidence: 99%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

140

120

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Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acylCoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets. ß 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 483-544, 2008

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“…In this context, several studies have shown that, in cells of the macrophage lineage, oxysterols can initiate specific signal transduction pathways, which are relevant to the development of atherosclerosis [176][177][178][179]. A recent study has demonstrated that an oxysterol mixture, of composition similar to that found in advanced human carotid plaques [173], can significantly contribute to destabilizing the fibrotic plaque, by increasing expression and activity of MMP-9, without interfering with expression and synthesis of TIMP-1 or TIMP-2.…”

Section: Introductionmentioning

confidence: 99%

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

Gargiulo¹,

Gamba²,

Poli³

et al. 2014

CPD

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Degradation of the extracellular matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair and remodeling. It is precisely regulated under physiological conditions, but when dysregulated it becomes a cause of many diseases, including atherosclerosis, osteoarthritis, diabetic vascular complications, and neurodegeneration. Various types of proteinases are implicated in extracellular matrix degradation, but the major enzymes are considered to be metalloproteinases such as matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase domain (ADAMs) that include ADAMs with a thrombospondin domain (ADAMTS).This review discusses involvement of the major metalloproteinases in some age-related chronic diseases, and examines what is currently known about the beneficial effects of their inhibitors, used as new therapeutic strategies for treating or preventing the development and progression of these diseases.

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Early Involvement of ROS Overproduction in Apoptosis Induced by 7-Ketocholesterol

Cited by 71 publications

References 19 publications

The role of oxysterols in control of endothelial stiffness

The role of oxysterols in control of endothelial stiffness

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

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