The Impact of RIPK1 Kinase Inhibition on Atherogenesis: A Genetic and a Pharmacological Approach

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.

Automated summary

The study investigates the effects of RIPK1 kinase activity on atherosclerosis and suggests that inhibiting RIPK1 kinase activity accelerates the progression of atherosclerosis.