背景:内皮细胞的代谢灵活性与其表型可塑性有关。Frataxin在决定内皮细胞的铁代谢和命运方面至关重要。本研究旨在研究内皮-间质转化(EndoMT)过程中共济失调蛋白介导的代谢重塑。
结果:内皮细胞特异性共济失调蛋白敲除和共济失调蛋白突变小鼠接受血管紧张素II诱导高血压。使用组织学和蛋白质表达分析评估EndoMT和心脏纤维化。使用海马XF96分析仪测量微血管内皮细胞中的脂肪酸氧化(FAO)。我们表明,对FAO的抑制伴随着血管紧张素II诱导的EndoMT。Frataxin基因敲除小鼠促进EndoMT,与血管紧张素II输注后心脏纤维化增加有关。血管紧张素II减少共济失调蛋白的表达,这导致线粒体铁过载和随后沉默蛋白3的羰基化。反过来,羰基化沉默酶3有助于赖氨酸189处的乙酰化共济失调蛋白,使其更容易降解。共轴蛋白/沉默蛋白3反馈环减少羟基辅酶A脱氢酶α亚基介导的FAO。此外,水飞蓟素是自由基的清除剂,恢复血管紧张素II诱导的FAO活性和沉默蛋白3和共济失调蛋白表达的减少,在体外和体内都能改善EndoMT。此外,frataxin突变小鼠显示EndoMT抑制和心脏纤维化改善。
结论:共济失调蛋白/沉默调节蛋白3反馈回路有可能通过改善FAO来减弱血管紧张素II诱导的EndoMT。
BACKGROUND: The metabolic flexibility of endothelial cells is linked to their phenotypic plasticity.
Frataxin is critical in determining the iron metabolism and fate of endothelial cells. This study aimed to investigate frataxin-mediated metabolic remodeling during the endothelial-to-mesenchymal transition (EndoMT).
RESULTS: Endothelial cell-specific
frataxin knockout and
frataxin mutation mice were subjected to angiotensin II to induce hypertension. EndoMT and cardiac fibrosis were assessed using histological and protein expression analyses. Fatty acid oxidation (FAO) in microvascular endothelial cells was measured using a Seahorse XF96 analyzer. We showed that inhibition of FAO accompanies angiotensin II-induced EndoMT. Frataxin knockout mice promote EndoMT, associated with increased cardiac fibrosis following angiotensin II infusion. Angiotensin II reduces
frataxin expression, which leads to mitochondrial iron overload and subsequent carbonylation of sirtuin 3. In turn, carbonylated sirtuin 3 contributes to the acetylated frataxin at lysine 189, making it more prone to degradation. The
frataxin/sirtuin 3 feedback loop reduces hydroxyl-CoA dehydrogenase α subunit-mediated FAO. Additionally, silymarin is a scavenger of free radicals, restoring angiotensin II-induced reduction of FAO activity and sirtuin 3 and frataxin expression, improving EndoMT both in vitro and in vivo. Furthermore,
frataxin mutation mice showed suppressed EndoMT and improved cardiac fibrosis.
CONCLUSIONS: The frataxin/sirtuin 3 feedback loop has the potential to attenuate angiotensin II-induced EndoMT by improving FAO.