Puylaert Pauline, Coornaert Isabelle, Neutel Cédric H G, Dondelinger Yves, Delanghe Tom, Bertrand Mathieu J M, Guns Pieter-Jan, De Meyer Guido R Y, Martinet Wim
Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Biomedicines. 2022 Apr 28;10(5):1016. doi: 10.3390/biomedicines10051016.
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 mutation, which prevents activation of RIPK1 kinase, on atherogenesis in ApoE mice. After 16 weeks of western-type diet (WD), atherosclerotic plaques from ApoE RIPK1 mice were significantly larger compared to ApoE RIPK1 mice (167 ± 34 vs. 78 ± 18 × 10 µm, = 0.01). Cell numbers (350 ± 34 vs. 154 ± 33 nuclei) and deposition of glycosaminoglycans (Alcian blue: 31 ± 6 vs. 14 ± 4%, = 0.023) were increased in plaques from ApoE RIPK1 mice while macrophage content (Mac3: 2.3 ± 0.4 vs. 9.8 ± 2.4%, = 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 Fbn1 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, = 0.004). In conclusion, inhibition of RIPK1 kinase activity accelerated plaque progression in ApoE RIPK1 mice and induced apoptosis in GSK'547-treated ApoE Fbn1 mice. Thus, without directly comparing the genetic and pharmacological studies, it can be concluded that targeting RIPK1 kinase activity does not limit atherogenesis.
受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）的酶活性驱动细胞凋亡和坏死性凋亡（一种受调控的坏死形式）。由于坏死性凋亡参与动脉粥样硬化斑块坏死核心的形成，我们研究了一种阻止RIPK1激酶激活的RIPK1突变对载脂蛋白E（ApoE）小鼠动脉粥样硬化发生的影响。在西式饮食（WD）喂养16周后，ApoE RIPK1小鼠的动脉粥样硬化斑块明显大于ApoE RIPK1小鼠（167±34 vs. 78±18×10 µm，P = 0.01）。ApoE RIPK1小鼠斑块中的细胞数量（350±34 vs. 154±33个细胞核）和糖胺聚糖沉积（阿尔新蓝染色：31±6 vs. 14±4%，P = 0.023）增加，而巨噬细胞含量（Mac3染色：2.3±0.4 vs. 9.8±2.4%，P = 0.012）减少。两组之间的斑块细胞凋亡无差异。相比之下，在晚期动脉粥样硬化模型ApoE Fbn1小鼠中，用GSK'547（10 mg/kg体重/天）对RIPK1激酶进行药理学抑制，在WD喂养20周后并未改变斑块大小，但诱导了细胞凋亡（TUNEL染色：136±20 vs. 62±9个细胞/mm，P = 0.004）。总之，抑制RIPK1激酶活性加速了ApoE RIPK1小鼠的斑块进展，并在GSK'547处理的ApoE Fbn1小鼠中诱导了细胞凋亡。因此，在没有直接比较基因和药理学研究的情况下，可以得出结论，靶向RIPK1激酶活性并不能限制动脉粥样硬化的发生。
