Catherine Reardon-Alulis, Ph.D.

Effect of Immune System and Apoproteins on Atherogenesis and Lipoprotein Assembly and the Role of apoE in Neurobiology.

Research Summary

There are two major areas of research in the laboratory.

Influence of the immune system on atherosclerosis. Atherosclerosis is now considered to be a chronic inflammatory response to hyperlipidemia. We are investigating the role of the immune system on the development and progression of atherosclerotic lesions using genetically modified mice that develop atherosclerosis. We have previously shown that in the absence of mature T and B cells atherosclerosis is reduced at some vascular sites and not others depending upon the gender and genetic background of the mice. Our current studies are aimed at determining the influence of specific cell of the adaptive and innate immune systems and the cytokines that they produce on atherosclerosis and lipoprotein metabolism. Our basic approach is to reconstitute the immune system of the immune deficient atherosclerotic mice with specific immune cells using bone marrow transplant or adoptive transfer of cells obtained from wild type, transgenic or knockout mice. In some cases cells will be infected with recombinant viruses expressing cytokines prior to transfer or the activity of cytokines blocked using specific inhibitors.

Influence of HDL on atherosclerosis. Humans have two HDL subclasses, HDL2 and HDL3. High HDL levels are atheroprotective and epidemiological evidence suggests that HDL2 maybe more atheroprotective than HDL3. We are first determining the domain(s) of the major HDL apoprotein, apoprotein A-I, which facilitate the formation of the HDL subclasses, with an emphasis in the role of the turns between the multiple amphipathic helices in apoprotein A-I. The apoprotein A-I mutants capable of forming each of the HDL subclasses will be expressed in atherosclerosis susceptible mice in order to determine the in vivo role of the subclasses in atherosclerosis. The HDL particles will also be characterized with their ability to participate in various aspects of reverse cholesterol transport, i.e. the process by which excess cellular cholesterol is transported to the liver. We are also investigating the role of SAA, a major protein associated with HDL during an acute phase response, as recent evidence suggests that some of the SAA isoforms may also promote cholesterol efflux from cholesterol-enriched macrophages.

Selected Papers

Reschly EJ, Sorci-Thomas M, Davidson WS, Meredith SC, Reardon CA, and Getz GS. (2002). Apolipoprotein alpha helices 7 and 8 modulate high density lipoprotein subclass distribution. J Biol Chem. 277:9645-9654.

Zhu B, Reardon CA, Getz GS, and Hui DY. (2002). Both apolipoprotein E- and immune-deficiency contribute exacerbated neointimal hyperplasia after vascular injury in mice. Arterioscler Thromb Vasc Biol. 22:450-455.

Bentley NM, LaDu MJ, Rajan C, Getz GS, Reardon CA. (2002). Apolipoprotein E structural requirements for the formation of SDS Stable complexes with beta-amyloid (1-40): the role of salt bridges. Biochem J 366:273-9.

Cabana VG, Reardon CA, Feng N, Lukens J, and Getz GS. (2003). Serum paraxonase: Effect of the apoprotein composition of HDL and the acute phase response. J Lipid Res. 44:780-792.

Reardon CA, Blachowicz L, Lukens J, Nissenbaum M, and Getz GS. (2003). Genetic background selectively influences innominate artery atherosclerosis: immune deficiency as probe. Arterioscler Thromb Vasc Biol. 23:1449-1454.

Peng D, Song C, Reardon CA, Liao S, and Getz GS. (2003). Lipoproteins produced by apoE-/- astrocytes infected with adenovirus expressing human apoE. J Neurochem. 86:1391-1402.

Cabana VG, Feng N, Reardon CA, Lukens J, Webb NR, de Beer FC, Getz GS (2004). Influence of apoA-I and apoE on the formation of serum amyloid A-containing lipoproteins in vivo and in vitro. J Lipid Res. 45:317-325.

VanderLaan PA, Reardon CA, Getz GS. (2004). Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 24:12-22

Getz GS, and Reardon CA. (2004). Paraoxonase, a cardioprotective enzyme: continuing issues. Curr Opin Lipidol. 15:261-267.

Reardon CA, Miller ER, Blachowicz L, Lukens J, Binder CJ, Witztum JL, and Getz GS. (2004). Autoantibodies to OxLDL fail to alter the clearance of injected OxLDL in apolipoprotein E deficient mice. J Lipid Res. 45:1347-1354.