Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Commun Biol. 2022 Apr 19;5(1):379. doi: 10.1038/s42003-022-03309-9.
Recent studies highlight the importance of lipotoxic damage in aortic cells as the major pathogenetic contributor to atherosclerotic disease. Since the STE20-type kinase STK25 has been shown to exacerbate ectopic lipid storage and associated cell injury in several metabolic organs, we here investigate its role in the main cell types of vasculature. We depleted STK25 by small interfering RNA in human aortic endothelial and smooth muscle cells exposed to oleic acid and oxidized LDL. In both cell types, the silencing of STK25 reduces lipid accumulation and suppresses activation of inflammatory and fibrotic pathways as well as lowering oxidative and endoplasmic reticulum stress. Notably, in smooth muscle cells, STK25 inactivation hinders the shift from a contractile to a synthetic phenotype. Together, we provide several lines of evidence that antagonizing STK25 signaling in human aortic endothelial and smooth muscle cells is atheroprotective, highlighting this kinase as a new potential therapeutic target for atherosclerotic disease.
最近的研究强调了脂肪毒性损伤在主动脉细胞中的重要性，这是动脉粥样硬化疾病的主要发病机制。由于 STE20 型激酶 STK25 已被证明会加剧几种代谢器官中的异位脂质储存和相关细胞损伤，因此我们在此研究其在血管主要细胞类型中的作用。我们通过小干扰 RNA 在暴露于油酸和氧化 LDL 的人主动脉内皮和平滑肌细胞中耗尽 STK25。在这两种细胞类型中，STK25 的沉默减少了脂质积累，并抑制了炎症和纤维化途径的激活，同时降低了氧化应激和内质网应激。值得注意的是，在平滑肌细胞中，STK25 的失活阻止了从收缩表型向合成表型的转变。总之，我们提供了几条证据表明，拮抗人主动脉内皮和平滑肌细胞中的 STK25 信号传导具有抗动脉粥样硬化作用，突出了这种激酶作为动脉粥样硬化疾病的新的潜在治疗靶点。
