Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis (2022)

Abstract

Background and aims: Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Genetic disruption of Tnf-alpha reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-alpha blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-alpha inhibition on plaque development in experimental atherosclerosis.

Results: 10 week old male Ldlr(-/-) mice were divided into 4 groups (n = 7-10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-alpha monoclonal antibody CNTO5048 (CNT) or a control IgG was administered.

Results: CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-alpha inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-alpha inhibitor treatment.

Conclusions: Although up to 12-week pharmacological inhibition of TNF-alpha in Ldlr(-/-) mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile.

Original languageEnglish
Pages (from-to)80-89
Number of pages10
JournalATHEROSCLEROSIS
Volume277
DOIs
Publication statusPublished - Oct-2018

Keywords

  • Atherosclerosis
  • Inflammation
  • TNF-alpha inhibitor
  • HUMAN-ENDOTHELIAL-CELLS
  • ANTI-TNF AGENTS
  • ADHESION MOLECULE-1
  • DEFICIENT MICE
  • DISEASES
  • INTERLEUKIN-6
  • INFLAMMATION
  • PROGRESSION
  • CYTOKINES
  • INHIBITION

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Oberoi, Raghav ; Vlacil, Ann-Kathrin ; Schuett, Jutta ; Schoesser, Florian ; Schuett, Harald ; Tietge, Uwe J. F. ; Schieffer, Bernhard ; Grote, Karsten. / Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis. In: ATHEROSCLEROSIS. 2018 ; Vol. 277. pp. 80-89.

@article{7c834451e141457da2d93c1fbb4b1c25,

title = "Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis",

abstract = "Background and aims: Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Genetic disruption of Tnf-alpha reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-alpha blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-alpha inhibition on plaque development in experimental atherosclerosis.Results: 10 week old male Ldlr(-/-) mice were divided into 4 groups (n = 7-10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-alpha monoclonal antibody CNTO5048 (CNT) or a control IgG was administered.Results: CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-alpha inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-alpha inhibitor treatment.Conclusions: Although up to 12-week pharmacological inhibition of TNF-alpha in Ldlr(-/-) mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile.",

keywords = "Atherosclerosis, Inflammation, TNF-alpha inhibitor, HUMAN-ENDOTHELIAL-CELLS, ANTI-TNF AGENTS, ADHESION MOLECULE-1, DEFICIENT MICE, DISEASES, INTERLEUKIN-6, INFLAMMATION, PROGRESSION, CYTOKINES, INHIBITION",

author = "Raghav Oberoi and Ann-Kathrin Vlacil and Jutta Schuett and Florian Schoesser and Harald Schuett and Tietge, {Uwe J. F.} and Bernhard Schieffer and Karsten Grote",

year = "2018",

month = oct,

doi = "10.1016/j.atherosclerosis.2018.08.030",

language = "English",

volume = "277",

pages = "80--89",

journal = "ATHEROSCLEROSIS",

issn = "0021-9150",

publisher = "ELSEVIER IRELAND LTD",

}

Oberoi, R, Vlacil, A-K, Schuett, J, Schoesser, F, Schuett, H, Tietge, UJF, Schieffer, B & Grote, K 2018, 'Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis', ATHEROSCLEROSIS, vol. 277, pp. 80-89. https://doi.org/10.1016/j.atherosclerosis.2018.08.030

Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis. / Oberoi, Raghav; Vlacil, Ann-Kathrin; Schuett, Jutta; Schoesser, Florian; Schuett, Harald; Tietge, Uwe J. F.; Schieffer, Bernhard; Grote, Karsten.

In: ATHEROSCLEROSIS, Vol. 277, 10.2018, p. 80-89.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis

AU - Oberoi, Raghav

AU - Vlacil, Ann-Kathrin

AU - Schuett, Jutta

AU - Schoesser, Florian

AU - Schuett, Harald

AU - Tietge, Uwe J. F.

AU - Schieffer, Bernhard

AU - Grote, Karsten

PY - 2018/10

Y1 - 2018/10

N2 - Background and aims: Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Genetic disruption of Tnf-alpha reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-alpha blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-alpha inhibition on plaque development in experimental atherosclerosis.Results: 10 week old male Ldlr(-/-) mice were divided into 4 groups (n = 7-10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-alpha monoclonal antibody CNTO5048 (CNT) or a control IgG was administered.Results: CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-alpha inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-alpha inhibitor treatment.Conclusions: Although up to 12-week pharmacological inhibition of TNF-alpha in Ldlr(-/-) mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile.

AB - Background and aims: Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Genetic disruption of Tnf-alpha reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-alpha blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-alpha inhibition on plaque development in experimental atherosclerosis.Results: 10 week old male Ldlr(-/-) mice were divided into 4 groups (n = 7-10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-alpha monoclonal antibody CNTO5048 (CNT) or a control IgG was administered.Results: CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-alpha inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-alpha inhibitor treatment.Conclusions: Although up to 12-week pharmacological inhibition of TNF-alpha in Ldlr(-/-) mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile.

KW - Atherosclerosis

KW - Inflammation

KW - TNF-alpha inhibitor

KW - HUMAN-ENDOTHELIAL-CELLS

KW - ANTI-TNF AGENTS

KW - ADHESION MOLECULE-1

KW - DEFICIENT MICE

KW - DISEASES

KW - INTERLEUKIN-6

KW - INFLAMMATION

KW - PROGRESSION

KW - CYTOKINES

KW - INHIBITION

U2 - 10.1016/j.atherosclerosis.2018.08.030

DO - 10.1016/j.atherosclerosis.2018.08.030

M3 - Article

VL - 277

SP - 80

EP - 89

JO - ATHEROSCLEROSIS

JF - ATHEROSCLEROSIS

SN - 0021-9150

ER -

Oberoi R, Vlacil A-K, Schuett J, Schoesser F, Schuett H, Tietge UJF et al. Anti-tumor necrosis factor-alpha therapy increases plaque burden in a mouse model of experimental atherosclerosis. ATHEROSCLEROSIS. 2018 Oct;277:80-89. https://doi.org/10.1016/j.atherosclerosis.2018.08.030

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