Endothelial versus global METRNL reveals importance of endothelial METRNL against atherosclerosis via mitochondrial homeostasis

We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E -deficient ( ApoE -/- ) mouse model and an in vitro oxidized low density lipoprotein (ox-LDL)-treated endothelial cell model, METRNL inhibited ox-LDL- or high fat diet-induced atherosclerosis by alleviating endothelial mitochondrial dysfunction and apoptosis which was achieved through a balance between PPARγ co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis and PTEN induced putative kinase protein 1 (PINK1)-Parkin-mediated mitophagy. These findings highlight the pivotal importance of endothelial METRNL against atherosclerosis by comparison with whole-body METRNL. This is the first demonstration of METRNL localization to mitochondria in endothelial cells and its role in maintaining endothelial mitochondrial stability against atherosclerosis. Furthermore, targeting METRNL to stabilize endothelial mitochondrial function represents a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.