Angelo M. Scanu, M.D.

Genetic Mechanisms in Dyslipoproteinemias in Humans; Metalloproteinases and Kringle-Containing Proteins; Proteoglycans in Athrogenesis

Research Summary

Apo(a) is a glycoprotein coded by a hypervariable apo(a) gene which is only present in humans, apes and some non-human primates. In human plasma, apo(a) is mostly linked by a single disulfide bridge to cholesterol-rich lipoprotein particles via their protein moiety, apoB100. High plasma levels of Lp(a), which are largely controlled by the apo(a) gene, are associated with an increased risk for cardiovascular disease by mechanisms yet to be established. A main goal of our research is to elucidate the molecular basis for the athero-thrombogenic potential of Lp(a) mostly related to apo(a). In the course of these studies we have discovered that apo(a) is a multi-kringle structure with a high degree of homology with plasminogen. The size of apo(a) varies among individuals from 300 to 800 kDa due to the number of a special class of kringle repeats. The relative large size of apo(a) has prevented an in depth investigation of its structure-function relationships. Recently, we found that inflammatory enzymes of the metalloproteinase family cleave apo(a) at specific linker sites generating fragments having distinct structural, functional and metabolic properties. Fragments of apo(a) are spontaneously present in humans and are also generated in mice when injected intravenously with apo(a). We are exploring the potential relationship between the activity of metalloproteinases and the athero-thrombogenic potential of apo(a) in the context of the recognized inflammatory theory of atherosclerosis. We are approaching the problem by in vitro studies using wild type and mutant apo(a) species, fragments of apo(a) and in vivo investigations using apo(a) transgenic crossed with mice deficient in given metalloproteinases by gene targeting. Complementary work is being conducted for defining the molecular basis for the established accumulation of apo(a) in human atheroma. We have shown that apo(a) binds to the protein core of aortic proteoglycans and now wish to establish the mechanisms underlying this binding also taking into account that proteoglycans may undergo degradation by the action of metalloproteinases at the inflammatory sites of the atheroma. These in vitro experiments will be complemented by studies to be conducted in apo(a) transgenic mice crossed with mice proteoglycan deficient by gene targeting.

Selected Papers

Klezovitch O., Edelstein C. and Scanu A.M. (2001). Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein(a): evidence for a critical involvement of elements of its C-terminal domain. J. Biol. Chem. 276: 46864-69.

Scanu A.M. and Hinman J. (2002). Monitoring statin treatment of hypercholesterolemic subjects having high plasma Lp(a) levels. Lipids, 37: 439-444.

Scanu A.M. (2003). Lipoprotein(a) and the athero-thrombotic process:mechanistic insights. Current Atherosclerosis Reports 5: 106-113.

Edelstein, C., Pfaffinger, D., Hinman, J., Miller, E., Lipkind, G., Tsimikas, S., Bergmark, C., Getz, G., Witztum, J., Scanu, A.M. (2003). Lysine-phosphatidylcholine adducts in kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein(a). J. Biol. Chem 278: 52841-47.

Formato, M., Farina, M., Spirito, R., Maggioni, M., Guarino, A., Cherchi, G.M., Biglioli, P., Edelstein, C., Scanu, A.M. (2004). Evidence for a poinflammatory and proteolytic environment in plaques from endarterectomy segments of human carotid arteries. Arterioscler Thromb Vasc Biol. 24:1-8.

Scanu, A.M., Chellamma, S. (2004). Cleavage of human apolipoprotein(a) coated on the surface of constituents of the vascular extracellular matrix by pancreatic elastase and metalloproteinase-12. Different partition between cleaved N-terminal and C-terminal domains. Vascular Disease Prevention, 1: 59-63.

Scanu, A.M., Hinman J., Pfaffinger D. and Edelstein C. (2004). Successful utilization of lyophilized lipoprotein(a) as a biological reagent. Lipid 39: 589-593.

Weiss, L.A., Abney M., Perry R., Scanu A.M., Cook E.H. and Ober C. (2004). Variations in ITGB3 is associated with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample Am J Genetics in press.