Oxidized phospholipid modification of lipoprotein(a): Epidemiology, biochemistry and pathophysiology

Oxidized phospholipids (OxPL) are key mediators of the pro-atherosclerotic effects of oxidized lipoproteins. They are particularly important for the pathogenicity of lipoprotein(a) (Lp(a)), which is the preferred lipoprotein carrier of phosphocholine-containing OxPL in plasma. Indeed, elevated levels of OxPL-apoB, a parameter that almost entirely reflects the OxPL on Lp(a), are a potent risk factor for atherothrombotic diseases as well as calcific aortic valve stenosis. A substantial fraction of the OxPL on Lp(a) are covalently bound to the KIV₁₀ domain of apo(a), and the strong lysine binding site (LBS) in this kringle is required for OxPL addition. Using apo(a) species lacking OxPL modification - by mutating the LBS - has allowed direct assessment of the role of apo(a) OxPL in Lp(a)-mediated pathogenesis. The OxPL on apo(a) account for numerous harmful effects of Lp(a) on monocytes, macrophages, endothelial cells, smooth muscle cells, and valve interstitial cells documented both in vitro and in vivo. In addition, the mechanisms underlying these effects have begun to be unraveled by identifying the cellular receptors that respond to OxPL, the intracellular signaling pathways turned on by OxPL, and the changes in gene and protein expression evoked by OxPL. The emerging picture is that the OxPL on Lp(a) are central to its pathobiology. The OxPL modification may explain why Lp(a) is such a potent risk factor for cardiovascular disease despite being present at concentrations an order of magnitude lower than LDL, and they account for the ability of elevated Lp(a) to cause both atherothrombotic disease and calcific aortic valve stenosis.