Fatty acids liberated from low-density lipoprotein trigger endothelial apoptosis via mitogen-activated protein kinases

Dersch, Katrin; Ichijo, Hidenori; Bhakdi, Sucharit; Husmann, Matthias

doi:10.1038/sj.cdd.4401633

Cited by 36 publications

(45 citation statements)

References 27 publications

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“…It was also evident that ONOO − -treated LDL did not induce LDL-R mediated uptake suggesting that it is not being endocytosed through an aggregated-LDL uptake mechanism. The in vivo LDL − nitration pattern and structure as well as ONOO − -modified LDL demonstrate that ONOO − is the most likely mechanism of protein nitration in vivo and suggests that protein unfolded LDL induces scavenger receptor dependent binding and uptake and is further supported by enzymatic modifications that induce protein unfolding [3,17]. Nitrated LDL is also involved in an LDL-R independent binding and uptake mediated by SR-A, LOX-1, and CD36, thus strengthening the pathophysiological significance of ONOO − -driven LDL modifications, its unfolding, and the pathogenesis of atherosclerosis.…”

Section: Specific Cellular Receptors For Ldl −mentioning

confidence: 99%

“…Reactive nitrogen species, especially peroxynitrite (ONOO − ), generated by the vascular endothelium, nitrate apo-B-100 in LDL particles [10,[12][13][14][15]. Enzyme-mediated modifications of LDL -accomplished through the action of ubiquitous hydrolytic enzymes-confer atherogenic properties to the lipoprotein particles [4,16]: s-phospholipase A 2 [3] and its free fatty acid product [17], cholesteryl esterases [4], plasmin [18], and matrix metalloproteinase -2 and -9 [18].…”

Section: Introductionmentioning

confidence: 99%

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LDL protein nitration: Implication for LDL protein unfolding

Hamilton

Asatryan

Nilsen

et al. 2008

Archives of Biochemistry and Biophysics

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Oxidatively-or enzymatically-modified low-density lipoprotein (LDL) is intimately involved in the initiation and progression of atherosclerosis. The in vivo modified LDL is electro-negative (LDL − ) and consists of peroxidized lipid and unfolded ApoB-100 protein. This study was aimed at establishing specific protein modifications and conformational changes in LDL − assessed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and circular dichroism analyses, respectively. The functional significance of these chemical modifications and structural changes were validated with binding and uptake experiments to-and by bovine aortic endothelial cells (BAEC).The plasma LDL − fraction showed increased nitrotyrosine and lipid peroxide content as well as a greater cysteine oxidation as compared with native-and total LDL. LC/MS/MS analyses of LDL − revealed specific modifications in the apoB-100 moiety, largely involving nitration of tyrosines in the α-helical structures and β 2 sheet as well as cysteine oxidation to cysteic acid in β 1 sheet. Circular dichroism analyses showed that the α-helical content of LDL − was substantially lower (~25%) than that of native LDL (~90%); conversely, LDL − showed greater content of β-sheet and random coil structure, in agreement with unfolding of the protein. These results were mimicked by treatment of LDL subfractions with peroxynitrite (ONOO − ) or SIN-1: similar amino acid modifications as well as conformational changes (loss of α-helical structure and gain in β-sheet structure) were observed. Both LDL − and ONOO − -treated LDL showed a statistically significant increase in binding and uptake to-and by BAEC compared to native LDL. We further found that most binding and uptake in control-LDL was through LDL-R with minimal oxLDL-R-dependent uptake. ONOO − -treated LDL was significantly bound and endocytosed by LOX-1, CD36 and SR-A with minimal contribution from LDL-R. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. It is suggested that lipid peroxidation and protein nitration may account for the mechanisms leading to apoB-100 protein unfolding and consequential increase in modified LDL binding and uptake to and by endothelial cells that is dependent on oxLDL scavenger receptors. NIH Public Access

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Section: Specific Cellular Receptors For Ldl −mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LDL protein nitration: Implication for LDL protein unfolding

Hamilton

Asatryan

Nilsen

et al. 2008

Archives of Biochemistry and Biophysics

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“…In vitro, FFAs have been shown to activate p38 MAPK in hepatocytes, cardiac myocytes, and endothelial cells (37)(38)(39)(40). p38 MAPK plays a central role in many inflammatory disorders, and p38 MAPK antagonists are currently being tested in clinical trials for treatment of rheumatoid arthritis, Alzheimer's disease, and inflammatory bowel disease (41).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta

et al. 2008

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OBJECTIVE-Obesity is associated with insulin resistance, hyperinsulinemia, elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic vascular disease (ASVD). A part of this increased risk may be due to enhanced activation of matrix metalloproteinases (MMPs). Here, we have examined the effects of physiologically elevated levels of insulin and FFA on three MMPs and their inhibitors (tissue inhibitors of MMP [TIMPs]) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping.RESEARCH DESIGN AND METHODS-Four-hour euglycemic-hyperinsulinemic clamps with infusion of saline/glycerol, lipid/heparin, or insulin with or without lipid/heparin were performed in alert unrestrained male rats.RESULTS-Hyperinsulinemia increased MMP-2 (ϳ6-fold), MMP-9 (ϳ13-fold), membrane type 1-MMP (MT1-MMP; ϳ8-fold) (all Western blots), and gelatinolytic activity (zymography) of MMP-2 (2-fold), while not affecting TIMP-1 and TIMP-2. Insulin increased IRS-1-associated PI 3-kinase (PI3K), extracellular signal-regulated kinases 1/2 (ERK1/2), and c-jun NH 2 -terminal kinase (JNK) (by Western blots with phospho-specific antibodies). FFA augmented the insulin-mediated increases in MMP-2 (from ϳ6-to ϳ11-fold), MMP-9 (from ϳ3-to ϳ23-fold), MT1-MMP (from ϳ8-to ϳ20-fold), MMP-2 gelatinolytic activity (from 2-to 3-fold), and JNK and p38 mitogen-activated protein kinase (MAPK) activities but decreased insulin-mediated activation of PI3K and ERK1/2. Raising FFA without raising insulin affected neither MMPs nor TIMPs.CONCLUSIONS-FFA augmented insulin stimulation of the MMP/TIMP balance of three proatherogenic MMPs and increased activities of two MAPKs (JNK and p38 MAPK), both of which are known to stimulate the production of proinflammatory cytokines. This may, over time, increase degradation of extracellular matrix and together with inflammatory changes promote development of ASVD. Diabetes 57:476-483, 2008 M any obese people are insulin resistant (1,2). Insulin resistance, on the other hand, is one of the most important risk factors for the development and progression of atherosclerotic vascular disease (ASVD) (3,4). The relationship between insulin resistance and ASVD, however, is complex. On one hand, insulin resistance is associated with several established risk factors for ASVD such as type 2 diabetes, hypertension, atherogenic dyslipidemia, and abnormalities of blood coagulation and fibrinolysis (5). On the other hand, these associations cannot completely explain the obesity/insulin resistance-related ASVD risk, suggesting that there may be other, as yet unidentified, ways in which insulin resistance increases this risk (6). Indeed, there are reasons to believe that insulin resistance may increase ASVD by promoting matrix metalloproteinase (MMP) activity. MMPs are enzymes with proteolytic activity against connective tissue proteins such as collagen, proteoglycans, and elastin and there is accumulating evidence suggesting that they play a key role in the development of atherosclerotic lesions (rev. in 7). For instanc...

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“…To date, the pro-apoptotic activity of different FFAs has been examined primarily in immortalized endothelial cell lines (EA.hy926, ECV304) and human umbilical vein endothelial cells (HUVECs) (3)(4)(5)(6). Studies involving target tissues directly affected by the metabolic syndrome are rare (7,16,17) and have not been performed in EPCs.…”

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confidence: 99%