Howard Kruth received his M.M.S. from Rutgers Medical School in 1973 and his M.D. from the University of Pennsylvania Medical School in 1975. He interned in the Department of Medicine at the University of Florida until 1976 when he joined the Laboratory of Cellular Metabolism at the NHLBI as a staff associate. Dr. Kruth returned to the University of Florida in 1978 for a residency in clinical pathology, then came back to the NHLBI as Senior Investigator in the Laboratory of Experimental Atherosclerosis in 1980. Dr. Kruth has received both the Public Health Service Meritorious Service Medal in 1998 and Commendation Medal in 2004. He has authored or co-authored over 100 publications and serves on several international advisory boards. Dr. Kruth is also a fellow of the American Heart Association’s Arteriosclerosis Council and a member of the North American Vascular Biology Organization and Society for Leukocyte Biology.
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. Depending on the macrophage phenotype, Dr. Kruth’s team has shown that fluid-phase pinocytosis can occur either by micropinocytosis within small vesicles called micropinosomes or by macropinocytosis within larger vacuoles called macropinosomes. Macropinosomes form from extended plasma membrane folds that fuse back with the plasma membrane, trapping extracellular fluid within the intracellular vacuoles that are formed.
In receptor-independent, fluid-phase pinocytosis, macrophages take up LDL as part of the fluid that they ingest during micropinocytosis and macropinocytosis. 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 recently shown that macrophages in mouse atherosclerotic lesions demonstrate fluid-phase uptake of fluorescent LDL-like surrogate nanoparticles.
Dr. Kruth now focuses on examining the signaling pathways that mediate fluid-phase pinocytosis in macrophages, a task made more challenging by the heterogeneity of macrophages and by the importance of pinocytosis in diverse biological processes. He and his colleagues have identified PI-3-kinase γ as a major contributor to LDL uptake in one type of macrophage. They are currently screening drugs and pursuing transgenic mouse studies to identify the signaling mechanisms involved.
In addition to accumulating cholesterol, macrophages are also capable of excreting it. In collaboration with colleagues, Dr. Kruth used a monoclonal antibody that specifically detects cholesterol aggregates in the form of microcrystalline arrays to show that after enrichment of macrophages with cholesterol, there is a concomitant accumulation of cholesterol in the extracellular matrix. Dr. Kruth’s laboratory showed that the actin cytoskeleton, likely regulated by Src tyrosine kinases, mediates this novel form of cholesterol deposition, and they are currently looking into the gene products responsible in more detail.