Mitochondria-Targeted Triphenylphosphonium-Hydroxytyrosol Prevents Lipotoxicity-Induced Endothelial Injury by Enhancing Mitochondrial Function and Redox Balance via Promoting FoxO1 and Nrf2 Nuclear Translocation and Suppressing Inflammation via Inhibiting p38/NF-кB Pathway

• Main Authors: Xuyun Liu (Author), Jing Gao (Author), Yizhen Yan (Author), Eleftheria A. Georgiou (Author), Jing Lou (Author), Mengya Feng (Author), Xing Zhang (Author), Feng Gao (Author), Jiankang Liu (Author), Ioannis K. Kostakis (Author), Lin Zhao (Author)
• Format: Book
• Published: MDPI AG, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Hyperlipidemia results in endothelial dysfunction, which is intimately associated with disturbed mitochondrial homeostasis, and is a real risk factor for cardiovascular diseases (CVDs). Triphenylphosphonium (TPP⁺)-HT, constructed by linking a mitochondrial-targeting moiety TPP⁺ to hydroxytyrosol (HT), enters the cell and accumulates in mitochondria and is thus an important candidate drug for preventing hyperlipidemia-induced endothelial injury. In the present study, we found that TPP-HT has a better anti-inflammatory effect than HT. In vivo, TPP-HT significantly prevented hyperlipidemia-induced adverse changes in the serological lipid panel, as well as endothelial and mitochondrial dysfunction of the thoracic aorta. Similarly, in vitro, TPP-HT exhibited similar protective effects in palmitate (PA)-induced endothelial dysfunction, particularly enhanced expression of the mitochondrial ETC complex II, recovered FoxO1 expression in PA-injured human aorta endothelial cells (HAECs) and promoted FoxO1 nuclear translocation. We further demonstrated that FoxO1 plays a pivotal role in regulating ATP production in the presence of TPP-HT by using the siFoxO1 knockdown technique. Simultaneously, TPP-HT enhanced Nrf2 nuclear translocation, consistent with the in vivo findings of immunofluorescence, and the antioxidant effect of TPP-HT was almost entirely blocked by siNrf2. Concomitantly, TPP-HT's anti-inflammatory effects in the current study were primarily mediated via the p38 MAPK/NF-κB signaling pathway in addition to the FoxO1 and Nrf2 pathways. In brief, our findings suggest that mitochondria-targeted TPP-HT prevents lipotoxicity induced endothelial dysfunction by enhancing mitochondrial function and redox balance by promoting FoxO1 and Nrf2 nuclear translocation.

Item Description

10.3390/antiox12010175
2076-3921