Expression of IMD-CBM peptide induces the autophagic degradation of CAV1 (caveolin 1) to inhibit LDL transcytosis and retard diabetic atherosclerosis

Atherosclerosis is attributable to a series of diabetes-related complications. CAV1 (caveolin 1)-mediated low-density lipoprotein (LDL) particle transcytosis across endothelial cells (ECs) is the initial step of atherosclerosis. MAP1LC3/LC3-interacting regions in the intramembrane domain (IMD) of CAV1 were buried in the caveolae and were not accessible for LC3B interaction, protecting CAV1 from autophagic degradation. However, the CSD domain of CAV1, exposed in the cytosol, directly interacted with a CBM domain of LC3B and inhibited autophagy. Therefore, the peptide IMD-CBM was constructed to induce the selective autophagic degradation of CAV1 and suppress LDL transcytosis in diabetic atherosclerosis. EC-specific expression of IMD-CBM was achieved using adenovirus. IMD-CBM directly interacted with CAV1 and LC3B in ECs, leading to the selective autophagic degradation of CAV1, activation of autophagy, and subsequent inhibition of LDL transcytosis. IMD-CBM promoted the autophagic degradation of CAV1 and consequently reduced the area of atherosclerotic plaques in <i>apoe</i>^-/- diabetic atherosclerotic mice. Overall, IMD-CBM expedited the autophagic degradation of CAV1 and inhibited high glucose-induced LDL transcytosis, highlighting its potential as a novel translatable strategy for the management of diabetic atherosclerosis.<b>Abbreviations</b>: ACTB: actin beta; AKT/protein kinase B: AKT serine/threonine kinase; AMPK: 5'-adenosine monophosphate-activated protein kinase; CAV1: caveolin 1; CBM: CAV1-binding motif; CRP: C-reactive protein; CSD: CAV1-scaffolding domain; GFP: green fluorescent protein; HUVEC: human umbilical vein endothelial cell; EC: endothelial cell; FITC: fluorescein isothiocyanate; IL6: interleukin 6; IL10: interleukin 10; IMD: intramembrane domain; LDL: low-density lipoprotein; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IκBα: NFKB inhibitor alpha; NO: nitric oxide; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PIK3C3/VPS34: phosphatidylinositol-3-kinase catalytic subunit type 3; Rapa: rapamycin; SAA: serum amyloid A; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TEM: transmission electron microscopy; TNF/TNF-α: tumor necrosis factor.