Journal
BIOMEDICINES
Volume 10, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines10051016
Keywords
RIPK1; atherosclerosis; necroptosis
Categories
Funding
- Fund for Scientific Research (FWO)-Flanders [EOS 30826052]
- Hercules Foundation [AUHA/13/03]
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The study investigates the effects of RIPK1 kinase activity on atherosclerosis and suggests that inhibiting RIPK1 kinase activity accelerates the progression of atherosclerosis.
RIPK1 (receptor-interacting serine/threonine-protein kinase 1) enzymatic activity drives both apoptosis and necroptosis, a regulated form of necrosis. Because necroptosis is involved in necrotic core development in atherosclerotic plaques, we investigated the effects of a RIPK1(S25D/S25D) mutation, which prevents activation of RIPK1 kinase, on atherogenesis in ApoE(- /-) mice. After 16 weeks of western-type diet (WD), atherosclerotic plaques from ApoE(-/-) RIPKS25D/S25D mice were significantly larger compared to ApoE(-/- )RIPK1(+/+) mice (167 +/- 34 vs. 78 +/- 18 x 10(3) mu m(2), p = 0.01). Cell numbers (350 +/- 34 vs. 154 +/- 33 nuclei) and deposition of glycosaminoglycans (Alcian blue: 31 +/- 6 vs. 14 +/- 4%, p = 0.023) were increased in plaques from ApoE(-/-)RIPK1(S25D/S25D) mice while macrophage content (Mac3: 2.3 +/- 0.4 vs. 9.8 +/- 2.4%, p = 0.012) was decreased. Plaque apoptosis was not different between both groups. In contrast, pharmacological inhibition of RIPK1 kinase with GSK'547 (10 mg/kg BW/day) in ApoE(-/-) RIPK1(S25D/S25D) mice, a model of advanced atherosclerosis, did not alter plaque size after 20 weeks WD, but induced apoptosis (TUNEL: 136 +/- 20 vs. 62 +/- 9 cells/mm(2), p = 0.004). In conclusion, inhibition of RIPK1 kinase activity accelerated plaque progression in ApoE(-/-)RIPK1(S25D/S25D) mice and induced apoptosis in GSK'547-treated ApoE(-/-) Fbn1(C1039G+/-) mice. Thus, without directly comparing the genetic and pharmacological studies, it can be concluded that targeting RIPK1 kinase activity does not limit atherogenesis.
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