Mitigating Vascular Inflammation by Mimicking AIBP Mechanisms: A New Therapeutic End for Atherosclerotic Cardiovascular Disease

Abstract

Atherosclerosis, characterized by the accumulation of lipoproteins and lipids within the vascular wall, underlies a heart attack, stroke, and peripheral artery disease. Endothelial inflammation is the primary component driving atherosclerosis, promoting leukocyte adhesion molecule expression (e.g., E-selectin), inducing chemokine secretion, reducing the production of nitric oxide (NO), and enhancing the thrombogenic potential. While current therapies, such as statins, colchicine, anti-IL1β, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, target systemic inflammation, none of them addresses endothelial cell (EC) inflammation, a critical contributor to disease progression. Targeting endothelial inflammation is clinically significant because it can mitigate the root cause of atherosclerosis, potentially preventing disease progression, while reducing the side effects associated with broader anti-inflammatory treatments. Recent studies highlight the potential of the APOA1 binding protein (AIBP) to reduce systemic inflammation in mice. Furthermore, its mechanism of action also guides the design of a potential targeted therapy against a particular inflammatory signaling pathway. This review discusses the unique advantages of repressing vascular inflammation or enhancing vascular quiescence and the associated benefits of reducing thrombosis. This approach offers a promising avenue for more effective and targeted interventions to improve patient outcomes.

Keywords: AIBP; ASCVD; inflamed EC-specific targeting; vascular inflammation.

Figure 1

(A). Lipoprotein penetration and retention in the sub-endothelium. Hyperlipidemia contributes to greater LDL and HDL presence in the subendothelial space, where they are rendered proinflammatory. These modified lipoproteins will be taken up by macrophages, which subsequently become lipid-laden foam cells. (B). AIBP impedes TLR4-mediated inflammatory signaling in myeloid cells. TLR4 dimerization is essential for the innate inflammatory response. AIBP binds TLR4, enabling a targeted cholesterol efflux, which disrupts TLR4 dimerization and represses signaling. This AIBP-mediated effects result in inhibited inflammatory responses. (C). AIBP regulation of lipid rafts via cytoskeleton rearrangement. AIBP binds PI(3)P, activating CDC42, and triggering actin polymerization, which consequently reduces the lipid raft levels. (D). AIBP regulates mitophagy. Mitochondrial AIBP binds PARKIN and MFN and increases the ubiquitination of MFN. Ubiquitinated MFN will recruit P62, which in turn facilitates the LC3 interactions, thereby targeting these mitochondria for degradation via autophagy.