159 - The role of macrophage RIPK1 in the development of atherosclerotic plaques in ApoE knockout mice (ID 397)
Abstract
Background and Aims
During atherogenesis, macrophages undergo necrosis and release their cytoplasmic content in the plaque, thereby forming a necrotic core. Further expansion of the necrotic core promotes plaque instability and rupture. Hence, targeting macrophage death is a promising strategy to stabilize plaques. Recently, necroptosis was discovered as a form of regulated necrosis. The formation of a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 pro-necrotic complex is crucial for necroptosis induction. This study aimed to investigate the impact of a macrophage-specific RIPK1 deletion on atherogenesis.
Methods
RIPK1F/FLysMCre+ApoE-/- and RIPK1+/+LysMCre+ApoE-/- mice were fed a western-type diet (WD) for 16 or 24 weeks to induce plaque formation.
Results
After 16 weeks WD, plaque area and percentage necrosis in RIPK1F/FLysMCre+ApoE-/- mice were significantly decreased (p<0.0001 and p=0.0005, respectively). Moreover, plaques of RIPK1F/FLysMCre+ApoE-/- mice showed increased TUNEL positivity (p=0.0005) and a decreased macrophage content (p=0.001). Additionally, NF-κB activation was inhibited in plaques of RIPK1F/FLysMCre+ApoE-/- mice (p=0.04). After 24 weeks WD, plaque size and necrosis did not alter between RIPK1F/FLysMCre+ApoE-/- and RIPK1+/+LysMCre+ApoE-/- mice (p=0.4 and p=0.6, respectively). Similar to plaques of RIPK1F/FLysMCre+ApoE-/- mice after 16 weeks WD, increased TUNEL positivity (p=0.008) was associated with a decrease in macrophage content (p=0.05). In vitro, macrophage RIPK1 deficiency inhibited NF-κB activation. Moreover, RIPK1 deletion increased the sensitivity of macrophages to apoptosis. However, it was not sufficient to inhibit necroptosis.
Conclusions
After 16 weeks WD, macrophage RIPK1 deficiency resulted in increased apoptosis, thereby slowing down plaque progression. However, after 24 weeks WD, plaque size of RIPK1F/FLysMCre+ApoE-/- mice did not differ anymore from the control mice.
