Abstract 234: Mitochondrial Reactive Oxygen Species Facilitate Phagocytosis During Initiation Of Atherosclerosis
| Autor: | Yiliang Chen, Jue Zhang, Jackie Chang, Mirza Beg, Yiqiong Zhao |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 42 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective: Atherosclerosis (AS) is associated with dyslipidemia, oxidative stress and foam cell accumulation within the AS plaques. Macrophage mitochondria dysfunction is commonly observed in both AS-prone animals and human patients with AS. But the contribution of macrophage mitochondria to AS development remain poorly understood. Our group previously showed that mitochondria continuously produce reactive oxygen species (mtROS) to drive macrophage activation and facilitate diet-induced AS. Here we aim to study the role of mtROS in phagocytosis, which could promote foam cell formation during atherogenesis. Approach and Results: We used pHrodo-Bioparticle and co-incubated with murine peritoneal macrophages. We then ran flowcytometry and quantified pHrodo (only emit fluorescence when pH is low as in the phagolysosomes) signals as phagocytosis efficiency. We found that oxidized LDL (oxLDL) but not native LDL or HDL pre-treatment stimulated 3-fold more phagocytosis by macrophages. We consolidated our results by showing oxLDL stimulated phagocytosis in a dose and time-dependent manner. Moreover, reducing mtROS either by MitoTempo, a mtROS scavenger, or by mitochondrial catalase overexpression significantly attenuated oxLDL effect on phagocytosis by ~40%. To explore the underlying molecular mechanism, we used different mitochondrial function inhibitors (etomoxir, rotenone, antimycin, oligomycin, FCCP) and found that etomoxir partially blocked (~25%) oxLDL-induced phagocytosis while antimycin promoted (~10%) this effect. In addition, we used confocal live cell imaging to show that mtROS facilitated the engulfment and formation of phagosomes. To further explore the physiological relevance, we conducted in vivo phagocytosis assay and demonstrated that mtROS are required for efficient phagocytosis in vivo. Initial atherogenic conditions increased phagocytosis by macrophages in the high fat diet-induced AS mouse ( apoe null) model. Conclusions: MtROS is essential for macrophage phagocytosis functions. Continuous stimulation of mtROS in macrophages could lead to too much large vesicles engulfment and lipid accumulation, which is responsible for foam cell formation during AS initiation. |
| Databáze: | OpenAIRE |
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