Restoring vascular endothelial autophagic flux reduces atherosclerotic lesions

Abstract

Atherosclerotic lesions preferentially develop in arterial areas exposed to low shear stress, where endothelial cells express a pro-inflammatory, apoptotic, and senescent phenotype. Endothelial cells exposed to atheroprone low shear stress present a defective autophagic flux, which favors a pro-inflammatory phenotype and the formation of atherosclerotic lesions. We tested the hypothesis that HDAC6 inhibition could restore adequate levels of autophagy in endothelial cells exposed to low shear stress. We found that blocking HDAC6 activity, either by pharmacological inhibition (Tubastatin-A) or genetic approaches (shHDAC6), raised levels of acetylated -tubulin, as well as LC3-II/I ratio, LC3 puncta area, nuclear TFEB translocation and autophagic flux in cultured endothelial cells exposed to low shear stress. This effect was associated with a reduced expression of inflammatory markers (ICAM-1, VCAM-1 and MCP-1) in TNF--stimulated cells. Impaired endothelial autophagic flux was restored in the aortic arch (atheroprone conditions) of HDAC6-/-mice, when compared to control littermates. Atherosclerotic plaque size was significantly decreased in the aortic arch of chimeric HDAC6-/-/ApoE-/- mice, transplanted with HDAC6+/+/ApoE-/- bone marrow, when compared to HDAC6+/+/ApoE-/- littermate controls. Taken together, these results indicate that HDAC6-inhibition may be an interesting strategy to restore endothelial autophagic flux, to help promote an atheroprotective endothelial phenotype despite unfavorable shear stress conditions.