A mechanistic study of mitochondria-targeted PCSK9 liposomes attenuate oxidative damage in carotid artery plaques.
Zhang Liwei, Chen Guanyu, Bai Yuhai, Li Qi
Abstract
Atherosclerotic plaque instability is a direct cause of cardiovascular and cerebrovascular events. In this study, a mitochondria-targeted liposome (LIP), modified with triphenylphosphonium (TPP) to enable specific mitochondrial delivery, was innovatively constructed to encapsulate a PCSK9 inhibitor (TPP-LIP@PCSK9). The aim was to explore a novel strategy for stabilizing plaques by restoring mitochondrial function in endothelial cells. Characterization results showed that TPP-LIP@PCSK9 possesses favorable nano-characteristics, and its targeting capability was confirmed through mitochondrial co-localization experiments. In an Apoe-/- mouse model, TPP-LIP@PCSK9 treatment significantly inhibited carotid artery plaque progression and reduced oxidative damage within the plaques. It markedly enhanced the activity of antioxidant enzymes (T-SOD, CAT) and decreased the level of lipid peroxidation products (MDA) in plaque tissue. Further analysis by Western blot and transcriptomics revealed that TPP-LIP@PCSK9 downregulated the mitochondrial damage marker proteins PINK1/Parkin, activated the Nrf2/UCP2-mediated antioxidant pathway, and modulated signaling pathways closely associated with oxidative stress and metabolism. This study is the first to report the direct role of PCSK9 in mitochondrial oxidative damage within plaque endothelial cells and to achieve effective intervention via nanotechnology, providing a new perspective for the treatment of atherosclerosis.
Key Findings
- Mitochondria-targeted liposomes encapsulating a PCSK9 inhibitor (TPP-LIP@PCSK9) effectively target mitochondria in endothelial cells.
- TPP-LIP@PCSK9 treatment inhibits carotid artery plaque progression and reduces oxidative damage in an Apoe-/- mouse model.
- The treatment activates the Nrf2/UCP2 antioxidant pathway, enhances antioxidant enzyme activity (T-SOD, CAT), decreases lipid peroxidation (MDA), and downregulates mitochondrial damage markers (PINK1/Parkin).
Clinical Significance
This study suggests that targeting mitochondrial oxidative stress via PCSK9 inhibition using nanotechnology offers a novel therapeutic approach to stabilize atherosclerotic plaques and potentially reduce cardiovascular events.
Citation
Zhang Liwei, Chen Guanyu, Bai Yuhaiet al.. A mechanistic study of mitochondria-targeted PCSK9 liposomes attenuate oxidative damage in carotid artery plaques. Journal of liposome research. 2026-Mar-29.