Chromatin modification by lipids and lipoprotein components: an initiating event in atherogenesis?

Zaina, Silvio; Døssing, Kristina B. V.; Lindholm, Marie; Lund, Gertrud

doi:10.1097/01.mol.0000180165.70077.ee

Cited by 27 publications

(14 citation statements)

References 34 publications

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“…Yet, perinuclear localization does not exclude a nuclear transport activity for ApoB, perhaps in concert with nucleolin, since the latter was shown to specifically bind ApoB-and ApoEcontaining lipoproteins and to shuttle between the nucleus and the cytoplasm (13). At any rate, our results do not support our original hypothesis that intracellular lipoprotein processing produces ApoB fragments that mediate the observed effects of lipoproteins on DNA methylation by direct interaction with chromatin (14). Furthermore, our recent data demonstrate that lipoprotein fatty acids induce changes in DNA methylation and histone modifications that are distinct from the ones induced by intact lipoprotein particles.…”

Section: Discussioncontrasting

confidence: 99%

Apolipoprotein B epitopes are present in nuclear preparations of human and mouse cells

Døssing

Zaina²

2009

Int J Mol Med

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Abstract. We previously showed that a native very lowdensity lipoprotein (VLDL)-and low-density lipoprotein (LDL)-rich mix induces global changes in DNA methylation in cultured THP-1 human macrophages. The exact molecular mechanisms for this response are not yet known. Previous studies showed that apolipoprotein B (ApoB) or its fragments can be localized in nuclei following cellular uptake, thus suggesting that ApoB may have a chromatin-modifying activity. To verify this hypothesis, we assessed whether ApoB epitopes are detected in THP-1 and mouse cell nuclei. Using a combination of immunoblotting, immunocytochemistry and chromatin immunoprecipitation, we showed that ApoB epitopes are present in THP-1 cell and mouse monocyte/ macrophage nuclear fractions, but are perinuclear rather than intranuclear. Our results are not consistent with a direct chromatin-ApoB interaction as an underlying mechanism for the observed epigenetic responses to lipoproteins in THP-1 cells.

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Section: Discussioncontrasting

confidence: 99%

Apolipoprotein B epitopes are present in nuclear preparations of human and mouse cells

Døssing

Zaina²

2009

Int J Mol Med

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“…8 However, progression of atherosclerosis begins with increased total plasma cholesterol levels. Hypercholesterolemia without appearance of any fatty streak lesion in the arteries alter gene expression 9 including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and P-selectin. Therefore, we hypothesized that hypercholesterolemia without atherosclerosis would effect 15-LO-1 expression.…”

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confidence: 99%

Hypercholesterolemia Enhances 15-Lipoxygenase–Mediated Vasorelaxation and Acetylcholine-Induced Hypotension

Aggarwal

Pfister

Campbell

2008

ATVB

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Objective-Arachidonic acid (AA) metabolites from 15-lipoxygenase-1 (15-LO-1), trihydroxyeicosatrienoic acid (THETA), and hydroxyepoxyeicosatrienoic acid (HEETA) relax arteries. We studied 15-LO-1 expression, THETA and HEETA synthesis, and their effect on arterial relaxations and blood pressure in hypercholesterolemic nonatherosclerotic rabbits. Methods and Results-Immunoblots, RTPCR analysis, and 14 C-AA metabolism revealed that hypercholesterolemia increased 15-LO-1 expression in the endothelium and THETA and HEETA synthesis in the arteries. Isometric tension recording, in presence of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitors, showed greater relaxations to acetylcholine (ACH) and AA (max 76.0Ϯ4.6% and 79.5Ϯ2.4%, respectively) in aortas from hypercholesterolemic rabbits compared with normal rabbits (max 39.1Ϯ2.8% and 39.9Ϯ2.2%, respectively). AA induced greater hyperpolarization in the smooth muscle cells of hypercholesterolemic aortas (Ϫ45.85Ϯ3.0 mV) compared with normal aortas (Ϫ31.45Ϯ1.9 mV). The ACH-and AA-relaxations were inhibited by 15-LO-1 inhibitors. ACH induced hypotensive responses were greater in hypercholesterolemic rabbits in absence (Ϫ54.9Ϯ3.3%) or presence (Ϫ48.5Ϯ3.2%) of NOS and COX-inhibitors compared with control rabbits (Ϫ31.6Ϯ3.3% and Ϫ24.3Ϯ1.6%, respectively). BW755C reduced these responses in hypercholesterolemic rabbits to Ϫ29.3Ϯ2.3%. Key Words: hypercholesterolemia Ⅲ 15-lipoxygenase Ⅲ endothelium-derived hyperpolarizing factors Ⅲ blood pressure Ⅲ arachidonic acid I n presence of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitors, agonist-induced relaxations are attributed to endothelium-derived hyperpolarizing factors (EDHFs) that regulate vascular tone. 1 Arachidonic acid (AA) metabolites from 15-lipoxygenase-1 (15-LO-1), 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA), and 11,12,15-trihydroxyeicosatrienoic acid (THETA) are EDHFs in rabbit arteries. [2][3][4] Other LO metabolites of AA, 15-hydroxyeicosatetraenoic acid (HETE), 12-HETE, and 15-hydroperoxyeicosatetraenoic acid (HpETE), are inactive in rabbit arteries. 5 15-LO-1 is important and sufficient to increase ACH-or AA-relaxations in rabbit arteries. 6,7 15-LO-1 expression increases in early atherosclerotic lesions in rabbit aorta. 8 However, progression of atherosclerosis begins with increased total plasma cholesterol levels. Hypercholesterolemia without appearance of any fatty streak lesion in the arteries alter gene expression 9 including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and P-selectin. Therefore, we hypothesized that hypercholesterolemia without atherosclerosis would effect 15-LO-1 expression. In the aortas from rabbits that were fed a 2% cholesterol diet for 2 weeks, ACH-relaxations sensitive to a LO inhibitor nordihydroguaiaretic acid (NDGA), and synthesis of AAmetabolites increased in the arteries. 10 NO-and prostaglandin (PG)-independent ACH-relaxations were also greater in the renal arteries from hypercholesterolemic rabbits. 11 ACHindu...

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“…These topics are beyond the scope of this manuscript and expertly reviewed elsewhere. 118,167 Epigenetic pathways offer a new perspective in the control of gene regulation with relevance to human cardiovascular disease and stroke research. As epigenetic processes are dynamic and respond to environmental cues, they provide the molecular substrate for understanding and experimentally verifying geneenvironment interactions.…”

Section: Concluding Remarks: the Emerging Field Of Stroke Epigeneticsmentioning

confidence: 99%

Epigenetics and stroke risk – beyond the static DNA code

Matouk¹,

Turgeon²,

Marsden³

2012

AGG

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Advances in high-throughput genome sequencing and genome-wide association studies indicate that only a fraction of estimated variability in stroke risk can be explained by genetic variation in protein-coding genes alone. Epigenetics is defined as chromatin-based mechanisms important in the regulation of gene expression that do not involve changes in the DNA sequence per se. Epigenetics represents an alternative explanation for how traditional risk factors confer increased stroke risk, provide a newer paradigm to explain heritability not explained by genetic variation, and provide insight into the link between how the environment of a cell can interact with the static DNA code. The nuclear-based mechanisms that contribute to epigenetic gene regulation can be separated into three distinct but highly interrelated processes: DNA methylation and hydroxymethylation; histone density and posttranslational modifications; and RNA-based mechanisms. Together, they offer a newer perspective on transcriptional control paradigms in blood vessels and provide a molecular basis for understanding how the environment impacts the genome to modify stroke susceptibility. This alternative view for transcriptional regulation allows a reassessment of the cis/trans model and even helps explain some of the limitations of current approaches to genetic-based screens. For instance, how does the environment exert chronic effects on gene expression in blood vessels after weeks or years? When a vascular cell divides, how is this information transmitted to daughter cells? This review provides an introduction to epigenetic concepts and a conceptual framework for understanding the shortcomings of an approach to stroke research that focuses solely on the static DNA code. Additionally, it will discuss classical and emerging mechanisms of epigenetic gene regulation that are especially relevant to large-vessel ischemic stroke.

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Chromatin modification by lipids and lipoprotein components: an initiating event in atherogenesis?

Cited by 27 publications

References 34 publications

Apolipoprotein B epitopes are present in nuclear preparations of human and mouse cells

Apolipoprotein B epitopes are present in nuclear preparations of human and mouse cells

Hypercholesterolemia Enhances 15-Lipoxygenase–Mediated Vasorelaxation and Acetylcholine-Induced Hypotension

Epigenetics and stroke risk – beyond the static DNA code

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Chromatin modification by lipids and lipoprotein components: an initiating event in atherogenesis?

Cited by 27 publications

References 34 publications

Apolipoprotein B epitopes are present in nuclear preparations of human and mouse cells

Apolipoprotein B epitopes are present in nuclear preparations of human and mouse cells

Hypercholesterolemia Enhances 15-Lipoxygenase–Mediated Vasorelaxation and Acetylcholine-Induced Hypotension

Epigenetics and stroke risk &ndash; beyond the static DNA code

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Epigenetics and stroke risk – beyond the static DNA code