Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis: Roles in Lipid Permeability, Lipid Retention, and Smooth Muscle Cell Proliferation

Tran‐Lundmark, Karin; Tran, Phan Kiet; Paulsson-Berne, Gabrielle; Fridén, Vincent; Soininen, Raija; Tryggvason, Karl; Wight, Thomas N.; Kinsella, Michael G.; Borén, Jan; Hedin, Ulf

doi:10.1161/circresaha.108.172833

Cited by 74 publications

(105 citation statements)

References 51 publications

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“…Heterozygous Pln -defi cient mice crossed to Apoe -null mice exhibited a signifi cant reduction in lesion size when fed chow for 12 weeks, indicating the important role of perlecan in the early phase of atherosclerosis development ( 47 ). In addition, mice expressing heparan sulfate-defi cient perlecan had reduced lesion formation with less lipoprotein binding in vitro ( 48 ), further confi rming the role of perlecan in lipid retention and atherosclerosis. Our results demonstrate that angII-induced perlecan accumulation and colocalization with apoB still remained within the lesions even upon 1D11 treatment, suggesting that perlecan is independent of TGF ␤ .…”

Section: Effects Of Tgf ␤ Neutralizing Antibody 1d11 On Plaque Composmentioning

confidence: 86%

Prevention of TGFβ induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr−/− mice

Tang

Wilson

Thompson

et al. 2013

Journal of Lipid Research

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Journal of Lipid Research Volume 54, 2013 2255(angII) is the major bioactive peptide and effector of RAS and acts via binding to AT1 receptors. Daugherty and Cassis ( 2 ) reported that chronic infusion of angII for 28 days potentiated atherosclerosis in Ldlr Ϫ / Ϫ mice receiving a high-fat diet. RAS blockade has been shown to not only attenuate the progression of atherosclerotic lesions in animals ( 3 ), but also has emerged as a therapy for human cardiovascular diseases ( 4, 5 ). Intensive research over the past decade reveals that the actions of angII on atherosclerosis include vascular infl ammation ( 6, 7 ), generation of reactive oxygen species ( 8 ), and alterations of endothelial function ( 9 ). AngII was also demonstrated to induce the expression of extracellular matrix (ECM) components in vascular smooth muscle cells (VSMCs), including collagen ( 10 ), laminin ( 11 ), and proteoglycans ( 12 ). However, the mechanisms underlying angII-accelerated atherosclerosis have not been fully elucidated.The "response to retention hypothesis" proposes that the subendothelial retention of the atherosclerotic lipoproteins (e.g., apoB-containing LDL) by ECM molecules such as proteoglycans via electrostatic attraction contributes to the initiation of atherosclerosis development ( 13,14 ). Biglycan is a member of chondroitin sulfate/dermatan sulfate containing small leucine-rich proteoglycans and binds apoB-containing lipoproteins ( 15 ). Biglycan was shown to be the proteoglycan most colocalized with apoB in both human and mouse atherosclerosis ( 16-18 ). Overexpression of human Bgn by rat smooth muscle cells (SMCs) results in increased lipoprotein binding on ECM Abstract Angiotensin II (angII) accelerates atherosclerosis, but the mechanisms are not fully understood. The aim of this study was to determine whether TGF ␤ is required for angIIinduced atherosclerosis. Ldlr -null mice fed a normal chow diet were infused with angII or saline for 28 days. A single injection of TGF ␤ neutralizing antibody 1D11 (2 mg/kg) prevented angII-induction of TGF ␤ 1 levels, and strikingly attenuated angII-induced accumulation of aortic biglycan content. To study atherosclerosis, mice were infused with angII or saline for 4 weeks, and then fed Western diet for a further 6 weeks. 1D11 had no effect on systolic blood pressure or plasma cholesterol; however, angII-infused mice that received 1D11 had reduced atherosclerotic lesion area by 30% ( P < 0.05). Immunohistochemical analyses demonstrated that angII induced both lipid retention and accumulation of biglycan and perlecan which colocalized with apoB. 1D11 strikingly reduced the effect of angII on biglycan but not perlecan. 1D11 decreased total collagen content ( P < 0.05) in the lesion area without changing plaque infl ammation markers (CD68 and CD45). Thus, this study demonstrates that neutralization of TGF ␤ attenuated angII stimulation of biglycan accumulation and atherogenesis in mice, suggesting that TGF ␤ -mediated biglycan induction is one of the mechanisms underlying angII-promot...

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Section: Effects Of Tgf ␤ Neutralizing Antibody 1d11 On Plaque Composmentioning

confidence: 86%

Prevention of TGFβ induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr−/− mice

Tang

Wilson

Thompson

et al. 2013

Journal of Lipid Research

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“…Interestingly, the heparan sulfate chains of the basement membrane proteoglycan perlecan promote atherosclerosis and play a role in lipid retention. 22 Since, collagen type IV has been shown to bind the heparan sulfate chains of perlecan, 23 this interaction could mediate a co-localization of collagen type IV and LDL, resulting in aldehyde modification of collagen type IV. The localization of native collagen type IV demonstrate that collagen type IV is not only present in the basement membrane, but also in the fibrous cap, 24 and could thus be modified by oxidized LDL bound to adjacent intimal proteoglycans.…”

Section: Discussionmentioning

confidence: 99%

Increased aldehyde-modification of collagen type IV in symptomatic plaques – A possible cause of endothelial dysfunction

et al. 2015

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Increased aldehyde-modification of collagen type IV in symptomatic plaques -A possible cause of endothelial dysfunction.Dunér, Pontus; Goncalves, Isabel; Grufman, Helena; Edsfeldt, Andreas; To, Fong; Nitulescu, Mihaela; Nilsson, Jan; Bengtsson, Eva Link to publication Citation for published version (APA): Dunér, P., Goncalves, I., Grufman, H., Edsfeldt, A., To, F., Nitulescu, M., ... Bengtsson, E. (2015). Increased aldehyde-modification of collagen type IV in symptomatic plaques -A possible cause of endothelial dysfunction. Atherosclerosis, 240(1), 26-32. DOI: 10.101626-32. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Abstract ObjectiveSubendothelial LDL-adhesion and its subsequent oxidation are considered as key events in the development of atherosclerotic lesions. During oxidation of LDL, reactive aldehydes such as malondialdehyde (MDA) are formed, which modify apolipoproteinB100. However, the possibility that these reactive aldehydes could leak out of the LDL-particle and modify surrounding extracellular matrix proteins has been largely unexplored. We have investigated if aldehyde-modification of collagen type IV, one of the major basement membrane components, in plaques is associated with cardiovascular events. MethodsThe amount of MDA-modified collagen type IV and native collagen type IV were determined in homogenates from 155 carotid artery lesions, removed by endarterectomy from patients with or without previous cerebrovascular events. ResultsPlaque MDA-collagen type IV, but not native collagen type IV, correlated with oxidized LDL (r=0.31, P<0.001) and lipoprotein-associated phospholipase A2 (r=0.44, P<0.001).MDA-collagen type IV was increased in lesions from symptomatic patients compared to lesions from asymptomatic patients. Autoantibodies against MDA-collagen type IV in plasma correlated with the amount of MDA-collagen type IV in lesions. MDA-modification of collagen type IV decreased endothelial cell attachment. In addition, culture of endothelial cells with MDA-modified collagen type IV increased vascular cell adhesion molecule expression and reduced the anti-coagulant proteins thrombomodulin and endothelial protein C receptor. In the lesions native collagen type IV, but not MDA-collagen type IV, was positively associated with thrombomodulin. Conclusion 3The present observations imply that aldehyde-modification of collagen type IV, associated with LDL oxidation, in atherosclerotic plaques may cause endothelial d...

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“…In this work, lipoprotein lipase was found to play a purely structural role in linking aggregated LDL to the matrix. Interestingly, arterial-wall matrix, lipoprotein lipase, and SMase have each been shown to contribute to retention of apoB-100-containing lipoproteins and atherogenesis in vivo ( 6,(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH

Sneck

Nguyen

Pihlajamaa

et al. 2012

Journal of Lipid Research

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Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis: Roles in Lipid Permeability, Lipid Retention, and Smooth Muscle Cell Proliferation

Cited by 74 publications

References 51 publications

Prevention of TGFβ induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr−/− mice

Prevention of TGFβ induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr−/− mice

Increased aldehyde-modification of collagen type IV in symptomatic plaques – A possible cause of endothelial dysfunction

Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH

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