Caveolin-1 in endothelial cells: A potential therapeutic target for atherosclerosis

Fig. 1. Schematic representation of Cav1 with membrane topology. Cav1 is a membrane protein of 178aa in length with an IMD (102-134aa) inserted into the plasma membrane, and both the N and C termini are expressed in the cytoplasm to form a unique hairpin loop structure. Cav1 contains six lysine sites (Lys5/26/30/39/47/57) at the N terminus that can be modified for ubiquitination; it is modified by phosphorylation at the tyrosine 14 and serine 80 sites, with three palmitoylation sites (Cys133/143/156) in the C-terminal structural domain and MAD (135-150aa) for membrane insertion. Its OD (61-101aa) is an oligomeric structural domain directing the homo-zwitterionization of Cav1 molecules and hetero-oligomerization of cholesterol, fatty acids, and others. The CSD (82-101aa) is located within the OD structural domain and Cav1 exerts different biological functions by binding to different proteins through the CSD. OD, oligomerization domain; CSD, caveolin scaffolding domain; IMD, intramembrane domain; MAD, membrane attachment domain.

Fig. 2. Mechanism of Cav1 induced endothelial dysfunction leading to AS. The main features of atherosclerosis are lipid accumulation and chronic inflammatory activation. When endothelial cells sense nutrient depletion, they activate mTORC1 signaling and inhibit AMPK signaling, thereby inhibiting the formation of ULK1 and Class III PI3K complexes, preventing the formation of autophagic phagocytic vesicles and thus inhibiting autophagy, resulting in reduced levels of protective intracellular autophagy to degrade excess cholesterol and damaged organelles, and reduced degradation of Cav1 through reduced autophagy, leading to increased LDL transcytosis across the endothelial cells. When endothelial cells respond to shear stress stimulation leading to a decrease in glycocalyx and a decrease in caveolae, the co-localization of caveolae with eNOS-pS1177 is impaired thereby attenuating NO signaling. Activation of TLR4 by LSS and thus NOX2 induces an increase in Cav1 phosphorylation leading to eNOS inactivation, while inflammatory cytokines induce inflammation in endothelial cells upregulating eNOS signaling leading to a massive accumulation of NO leading to a state of oxidative stress in…