PARP inhibition in atherosclerosis and its effects on dendritic cells, T cells and auto-antibody levels
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August 8, 2011
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© I. Holzap fel Publishers 2011
EurJ i\·lcd Res (2011 ) 16:367-374
PARP I NHIBITION IN ATHEROSCLEROSIS AND ITS EFFECTS ON DENDRITIC CELLS,
T CELLS AND AUTO -ANTIBODY LEVELS
C Erbel 1,J Achenbachl, M. Akhavanpoorl, T. J. D englerl , F Lasitsch ka2, C A G leissnerl, F Beal, H. A. Katusl, G. Szabo3 1 Department of
Cardiology, 2lnsLitute of Pathology, 3Dcpartment of Cardiac Surgery, Univc.rsity of H eidelberg, Germany
Abstract Olljective: Atherosclerosis is a chronic inflammatory process. Poly(A DP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to D A repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood. Methods: Male Apoe-1· mice o n a western diet were treated with the PARP inhibitor l N0-1001 (n = 15), while the control g roup (n = 15) received 5% glucose solution for 10 weeks. Remits: Inh ibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Imm unohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, I 0 -1 001 red uced number of cells (p 0.04), g rade of activation, represented by T/12 (p 0.04) and Cd83 (p = 0.03), and g rade of attraction, represented by Niip3a (p = 0.02) in the plaque. Furthermore, l N0-1001 decreased number ofT lym phocyte (p = 0.003) in the lesio n and grade of activation after stimulation with oxLDL in vitro. Mo reover, serum IgM antibody levels to oxLDL were significantly lower in IN0-1001 treated mice (p = 0.03). Cot1clttsio11s: Functio nal blockade of PARP by l N 0 1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechani sms also moderated due to modulation of D C and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxJ DL.
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Kry 1110rds: PARP, atherosclerosis, inflammation, oxLDL, dendritic cells, T cells I NTRODUCTION
A chro nic (auto)immunc response o f the arterial wall is a critical mechanism in the development of atherosclerosis [1, 2]. The disease process is associated with local fo rmation of modified auto-antigens like oxidized low-density lipoprotein (oxLDL), that are targeted by both the innate and adaptive immune system[2]. Inflammatory cells such as macrophages (M0), 'f-lymphocytes and dendritic cells (DC) are believed to be mainly involved in the initiation and prog ression of atherogenesis l2, 31Free radicals r eact with key organic substrates such as lipids to generate oxLDL. Oxidation of these bio-
molecules may impair their biological function and may contribute to initiation o r p rogression of atherosclerosis. l'ree radicals further interact with isolated or cellular DNA eventually lead ing to DNA strand breaks and /or base modifications [4]. Cells can respond to D r A strand damage by subsequent activation of the nuclear enzyme p oly(i\DPribose) polymerase-1 (PARP1) l4]. PARP-1 functions primarily as a D NA damage sen sor in the nucleus and mediate
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