Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China.
J Am Heart Assoc. 2024 Aug 6;13(15):e034316. doi: 10.1161/JAHA.124.034316. Epub 2024 Jul 18.
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).
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.
The frataxin/sirtuin 3 feedback loop has the potential to attenuate angiotensin II-induced EndoMT by improving FAO.
内皮细胞的代谢灵活性与其表型可塑性有关。铁蛋白在决定内皮细胞的铁代谢和命运方面至关重要。本研究旨在探讨铁蛋白介导的内皮细胞向间充质转化（EndoMT）过程中的代谢重塑。
采用血管紧张素 II 诱导内皮细胞特异性铁蛋白敲除和铁蛋白突变小鼠发生高血压。通过组织学和蛋白表达分析评估 EndoMT 和心脏纤维化。使用 Seahorse XF96 分析仪测量微血管内皮细胞中的脂肪酸氧化（FAO）。结果表明，FAO 抑制伴随着血管紧张素 II 诱导的 EndoMT。铁蛋白敲除小鼠促进 EndoMT，伴随血管紧张素 II 输注后心脏纤维化增加。血管紧张素 II 降低铁蛋白表达，导致线粒体铁过载和随后的 Sirtuin 3 碳化。反过来，碳化的 Sirtuin 3 导致赖氨酸 189 乙酰化的铁蛋白增加，使其更容易降解。铁蛋白/Sirtuin 3 反馈环降低羟基-CoA 脱氢酶 α 亚基介导的 FAO。此外，水飞蓟素是自由基的清除剂，可恢复血管紧张素 II 诱导的 FAO 活性和 Sirtuin 3 和铁蛋白表达降低，改善体外和体内的 EndoMT。此外，铁蛋白突变小鼠表现出抑制的 EndoMT 和改善的心脏纤维化。
铁蛋白/Sirtuin 3 反馈环通过改善 FAO 有潜力减轻血管紧张素 II 诱导的 EndoMT。
