Endogenous Neutralizing Antibodies Against Platelet-Derived Growth Factor-AA Inhibit Atherogenesis in the Cholesterol-Fed Rabbit

Lamb, David; Avades, Tony; Ferns, Gordon A.

doi:10.1161/01.atv.21.6.997

Cited by 15 publications

(13 citation statements)

References 27 publications

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“…12 Recent studies suggest that an overactivated PDGF system may play a role in the development of atherosclerosis in the context of hyperlipidemia. [13][14][15][16] The role of PDGF in atherosclerosis in the diabetic context remains unknown. This area of research has been hampered by a lack of an appropriate animal model.…”

Section: See Page 801mentioning

confidence: 99%

“…Specifically, clinical and experimental studies have shown that PDGF has a role in the development of atherosclerosis in the context of hyperlipidemia. [13][14][15][16] PDGF-A and PDGF-B mRNA levels are increased in circulating mononuclear cells of hypercholesterolemic and hyperlipidemic patients. 13 In rabbits fed with a high-cholesterol diet, immunization against PDGF-AA 14 or against PDGF-BB 15 reduces the size of aortic atherosclerotic lesions.…”

Section: Lassila Et Al Imatinib and Diabetic Atherosclerosis 939mentioning

confidence: 99%

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Imatinib Attenuates Diabetes-Associated Atherosclerosis

Lassila

Allen

Cao

et al. 2004

ATVB

129

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Objective-Diabetes is associated with accelerated atherosclerosis, the major factor contributing to increased mortality and morbidity in the diabetic population. The molecular mechanisms by which diabetes promotes atherosclerosis are not fully understood. Platelet-derived growth factor has been shown to play a major role in the pathology of vascular diseases, but whether it plays a role in atherosclerosis associated with diabetes remains unknown. The aims of this study were to assess whether platelet-derived growth factor-dependent pathways are involved in the development of diabetes-induced atherosclerosis and to determine the effects of platelet-derived growth factor receptor antagonism on this disorder. Methods and Results-Diabetes was induced by injection of streptozotocin in 6-week-old apolipoprotein E knockout mice.Diabetic animals received treatment with a tyrosine kinase inhibitor that inhibits platelet-derived growth factor action, imatinib (STI-571, 10 mg/kg per day), or no treatment for 20 weeks. Nondiabetic apolipoprotein E knockout mice served as controls. Induction of diabetes was associated with a 5-fold increase in plaque area in association with an increase in aortic platelet-derived growth factor-B expression and platelet-derived growth factor-␤ receptor phosphorylation as well as other prosclerotic and proinflammatory cytokines. Imatinib treatment prevented the development of atherosclerotic lesions and diabetes-induced inflammatory cytokine overexpression in the aorta. Key Words: atherosclerosis Ⅲ diabetes mellitus Ⅲ apolipoprotein E knockout mice Ⅲ platelet-derived growth factor Ⅲ vasculature P atients with type 1 and type 2 diabetes are at greater risk for atherosclerosis than nondiabetic subjects. 1 It has been estimated that 70% to 75% of adults with diabetes will die from cardiovascular diseases. 2,3 After correction for the other major risk factors, dyslipidemia, hypertension, and obesity, diabetes remains an independent risk factor for atherosclerosis. 4,5 The molecular mechanisms responsible for the accelerated progression of atherosclerosis as observed in diabetes remain to be fully delineated. Conclusions-Tyrosine

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Section: See Page 801mentioning

confidence: 99%

Section: Lassila Et Al Imatinib and Diabetic Atherosclerosis 939mentioning

confidence: 99%

Imatinib Attenuates Diabetes-Associated Atherosclerosis

Lassila

Allen

Cao

et al. 2004

ATVB

129

View full text Add to dashboard Cite

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“…PDGF has long been recognized as a powerful VSMC mitogen [3] and the induction of PDGF receptors in VSMCs during atherogenesis has been demonstrated in several studies [4,5]. Blockade of PDGF, whether by anti-PDGF antibody [6][7][8], PDGF receptor antisense therapy [9,10], or chimeric knockout in mice [11], reduces lesion formation after vascular injury. Ligand binding to the PDGF receptor causes tyrosine autophosphorylation and Address correspondence to: Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322,, e-mail: kgriend@emory.edu.…”

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confidence: 99%

Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells

Jay

Papaharalambus

Seidel-Rogol

et al. 2008

Free Radical Biology and Medicine

159

137

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The proliferation of vascular smooth muscle cells is important in the pathogenesis of many vascular diseases. Reactive oxygen species (ROS) produced by NADPH oxidases in smooth muscle cells have been shown to participate in signaling cascades regulating proliferation induced by platelet-derived growth factor (PDGF), a powerful smooth muscle mitogen. We sought to determine the role of Nox5 in the regulation of PDGF-stimulated human aortic smooth muscle cell (HASMC) proliferation. Cultured HASMC were found to express four isoforms of Nox5. When HASMC stimulated with PDGF were pretreated with N-acetyl cysteine (NAC), proliferation was significantly reduced. Proliferation induced by PDGF was also heavily dependent on JAK/STAT activation, as the JAK inhibitor, AG490, was able to completely abolish PDGF-stimulated HASMC growth. Specific knockdown of Nox5 with a siRNA strategy reduced PDGF-induced HASMC ROS production and proliferation. Additionally, siRNA to Nox5 inhibited PDGF-stimulated JAK2 and STAT3 phosphorylation. ROS produced by Nox5 play an important role in PDGF-induced JAK/STAT activation and HASMC proliferation. KeywordsNADPH oxidase; reactive oxygen species; Nox5; vascular smooth muscle cells; proliferation In atherosclerosis and restenosis after percutaneous coronary intervention, cytokines elaborated by both vascular cells and cells invading the vessel wall induce vascular smooth muscle proliferation and contribute to lesion formation. In the normal vessel wall, smooth muscle cells (SMCs) maintain and regulate vascular tone. However, VSMCs change their phenotype to a synthetic, proliferative state when stimulated by a number of different growth factors.One such growth factor, platelet-derived growth factor (PDGF), is expressed by all vascular cell types [1,2] and by invading inflammatory cells, such as monocytes and lymphocytes, in atherosclerosis [1]. PDGF has long been recognized as a powerful VSMC mitogen [3] and the induction of PDGF receptors in VSMCs during atherogenesis has been demonstrated in several studies [4,5]. Blockade of PDGF, whether by anti-PDGF antibody [6][7][8], PDGF receptor antisense therapy [9,10], or chimeric knockout in mice [11], reduces lesion formation after vascular injury. Ligand binding to the PDGF receptor causes tyrosine autophosphorylation and Address correspondence to: Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322,, e-mail: kgriend@emory.edu. 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. With regard to PDGF signaling, Nox5 is of particular interest because it...

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“…23 Protracted lesion formation requires a prolonged period of treatment and poses problems for experimental investigation, particularly with the administration of blocking antibodies. Studies in which endogenous neutralizing antibodies were induced in rabbits before initiation of the atherosclerotic diet 24,25 and PDGF receptor antibodies were administered long term in the ApoE null mouse model of atherosclerosis 26 have suggested the possibility that blockade of PDGF or the PDGF ␤-receptor can reduce lesion size. In this study, we have examined lesions in detail in ApoE Ϫ/Ϫ mice at extended time points and used two different approaches to test the role of PDGF in SMC accumulation in advanced lesions of atherosclerosis: hematopoietic chimeras lacking PDGF-B in their circulating cells and mice treated daily with a PDGF receptor antagonist.…”

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confidence: 99%

“…Our results contrast with recent reports from two groups that blockade of PDGF can decrease the size of lesions of atherosclerosis. 24 -26 In the rabbit studies, in which endogenous antibodies were induced by immunization with either PDGF-AA 25 or PDGF-BB, 24 lesions were evaluated 12 to 18 weeks after initiation of a 1% cholesterol diet. Lesion area evaluated by oil red O staining of the entire aorta shows a decrease of approximately 30%, and cross-sectional quantitation of aortic lesion-media ratios at a single site suggests up to 95% reduction.…”

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confidence: 99%