- Howard S. Kruth, M.D. Research
The cause of most heart attacks and strokes, atherosclerotic plaques in blood vessel walls accumulate cholesterol primarily from circulating low-density lipoproteins (LDL), also known as “bad cholesterol.” Dr. Kruth’s research focuses on understanding this process of cholesterol accumulation and plaque formation.
Scientists have known for some time that macrophages, a type of inflammatory cell, take up LDL to become foamy, cholesterol-laden cells within plaques. Dr. Kruth and his colleagues have demonstrated an alternative mechanism for macrophage foam cell formation that does not depend on LDL modification or macrophage receptors. By this mechanism, macrophages show uptake and degradation of native unmodified LDL by receptor-independent, fluid-phase pinocytosis. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques without requiring oxidative modification of LDL. Dr. Kruth’s laboratory has shown that macrophages in atherosclerotic lesions demonstrate fluid-phase uptake of fluorescent LDL-like surrogate nanoparticles.
In addition to accumulating cholesterol, macrophages are also capable of excreting it. In collaboration with colleagues, Dr. Kruth used a monoclonal antibody that specifically labels ordered arrays of unesterified cholesterol molecules to show that after enrichment of macrophages with cholesterol, there is a concomitant accumulation of cholesterol in the extracellular matrix. This research has shown that ABCA1 (and additionally ABCG1 in the mouse) functions in macrophage extracellular deposition of this cholesterol, and the drug, probucol, an inhibitor of ABCA1, blocks this cholesterol deposition. The extracellular cholesterol deposits can be mobilized by HDL. However, if not mobilized, buildup of extracellular unesterified cholesterol could be cytotoxic and promote the development of plaques. Thus, despite lowering HDL levels, the anti-atherogenic property of probucol is potentially due to its blocking macrophage deposition of extracellular unesterified cholesterol. Dr. Kruth is investigating this possibility as well as the chemical and structural characteristics of the deposited cholesterol.