Low-density lipoproteins (LDL cholesterol) are involved in the progressive damage to blood vessel walls that leads to atherosclerosis. The initial presence of oxidatively damaged LDL can cause a cascade of inflammation responses and further retention of LDL in the inflamed area. Macrophage cells arrive to clean up, some of which are overwhelmed by the amount of LDL to deal with and die. Their debris attracts more macrophages and changes local cell behavior, and all of this leads to a dysfunctional remodeling of the blood vessel wall and eventual growth of fatty plaques that can block the blood vessel or break off to cause a blockage elsewhere.
One source of damaged LDL is the small population of cells with dysfunctional, damaged mitochondria that exist in older people. Getting rid of those through some form of repair treatment yet to be developed would help the issue. The authors of this open access review paper propose interfering elsewhere in the process, targeting the molecular biochemistry involved in other aspects of damaged LDL behavior in the blood vessel wall:
An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted 'response-to-retention hypothesis', LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis.
Although the molecular mechanism of LDL retention and lipid droplet formation in the arterial subendothelium is not fully understood, it is increasingly clear that aggregation and fusion of modified LDLs prevent their exit from the arterial wall and contribute to atherogenesis. In contrast to modified LDLs, native LDLs do not readily aggregate or fuse under physiological conditions, suggesting that lipoprotein modifications drive these transitions. Many aspects of these reactions remain unclear, e.g., how do the apparently disparate chemical or physical modifications exert similar structural responses in LDL? Is there a synergy among numerous factors that influence LDL fusion? Which enzymatic or nonenzymatic modifications are particularly important in promoting or preventing LDL fusion in vivo? What are specific steps in LDL aggregation, fusion, and lipid droplet formation, and what therapeutic agents can block these pathogenic processes? These and other unanswered questions reflect the fact that atherosclerosis is a very complex chronic disease that can be influenced by an immense number of factors, many of which are not well understood.