The Function and Distribution of Apolipoprotein A1 in the Artery Wall are Markedly Distinct from those in Plasma
Background—Prior studies show apolipoprotein A1 (apoA1) recovered from human atherosclerotic lesions is highly oxidized. Ex vivo oxidation of apoA1 or high density lipoprotein (HDL) cross-links apoA1 and impairs lipid binding, cholesterol efflux and lecithin cholesterol acyltransferase (LCAT) activities of the lipoprotein. Remarkably, no studies to date directly quantify either the function or HDL particle distribution of apoA1 recovered from the human artery wall.
Methods and Results—A monoclonal antibody (mAb 10G1.5) was developed that equally recognizes lipid-free and HDL-associated apoA1 in both native and oxidized forms. Examination of homogenates of atherosclerotic plaque-laden aorta showed >100-fold enrichment of apoA1 compared to normal aorta (P<0.001). Surprisingly, buoyant density fractionation revealed only a minority (<3% of total) of apoA1 recovered from either lesions or normal aorta resides within an HDL-like particle (1.063 ≤ d ≤ 1.21). In contrast, the majority (>90%) of apoA1 within aortic tissue (normal and lesions) was recovered within the lipoprotein-depleted fraction (d>1.21). Moreover, both lesion and normal artery wall apoA1 is highly cross-linked (50-70% of total), and functional characterization of apoA1 quantitatively recovered from aorta using mAb 10G1.5 showed ~80% lower cholesterol efflux activity and ~90% lower LCAT activity relative to circulating apoA1.
Conclusions—The function and distribution of apoA1 in human aorta are quite distinct from those found in plasma. The lipoprotein is markedly enriched within atherosclerotic-plaque, predominantly lipid-poor, not associated with HDL, extensively oxidatively cross-linked, and functionally impaired.
- Received March 16, 2013.
- Revision received August 5, 2013.
- Accepted August 9, 2013.