Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent

Login or register to view PDF.
Abstract

Abstract

Back0ground

The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-IM) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice ├óÔé¼ÔÇ£ a model which is most adequately mimicking the clinical setting.

Pages

Methods and results
Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-IM or green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western Diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic en face analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-IM by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.

Conclusion
Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-IM each significantly reduced atherosclerosis progression to a similar extent.

Background
Apolipoprotein A-I (wtApoA-I) is the primary protein component of high density lipoproteins (HDL) [1] and like HDL cholesterol is inversely associated with atherosclerotic cardiovascular disease. Transgenic overexpression of wtApoA-I in liver substantially reduces progression of atherosclerosis in mice [2,3] and rabbits [4]. Furthermore, somatic gene transfer of wtApoA-I to liver using adenoviral vectors reduces progression [5,6] and induces regression [7] of atherosclerosis.

Pages

References
  1. Lewis GF, Rader DJ: New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005, 96:1221-32.
  2. Rubin EM, Krauss RM, Spangler EA, Verstuyft JG, Clift SM: Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 1991, 353:265-7.
  3. Plump AS, Scott CJ, Breslow JL: Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci USA 1994, 91:9607-11.
  4. Duverger N, Kruth H, Emmanuel F, Caillaud JM, Viglietta C, Castro G, Tailleux A, Fievet C, Fruchart JC, Houdebine LM, et al.: Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation 1996, 94:713-7.
  5. Benoit P, Emmanuel F, Caillaud JM, Bassinet L, Castro G, Gallix P, Fruchart JC, Branellec D, Denefle P, Duverger N: Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. Circulation 1999, 99:105-10.
  6. Belalcazar LM, Merched A, Carr B, Oka K, Chen KH, Pastore L, Beaudet A, Chan L: Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Circulation 2003, 107:2726-32.
  7. Tangirala RK, Tsukamoto K, Chun SH, Usher D, Pure E, Rader DJ: Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999, 100:1816-22.
  8. Chiesa G, Sirtori CR: Apolipoprotein A-I(Milano): current perspectives. Curr Opin Lipidol 2003, 14:159-63.
  9. Shah PK, Nilsson J, Kaul S, Fishbein MC, Ageland H, Hamsten A, Johansson J, Karpe F, Cercek B: Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation 1998, 97:780-5.
  10. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, et al.: Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. Jama 2003, 290:2292-300.
  11. Wang L, Sharifi BG, Pan T, Song L, Yukht A, Shah PK: Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice. J Am Coll Cardiol 2006, 48:1459-68.
  12. Parolini C, Chiesa G, Gong E, Caligari S, Cortese MM, Koga T, Forte TM, Rubin EM: Apolipoprotein A-I and the molecular variant apoA-I(Milano): evaluation of the antiatherogenic effects in knock-in mouse model. Atherosclerosis 2005, 183:222-9.
  13. Snyder RO, Miao C, Meuse L, Tubb J, Donahue BA, Lin HF, Stafford DW, Patel S, Thompson AR, Nichols T, et al.: Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med 1999, 5:64-70.
  14. Chen SJ, Rader DJ, Tazelaar J, Kawashiri M, Gao G, Wilson JM: Prolonged correction of hyperlipidemia in mice with familial hypercholesterolemia using an adeno-associated viral vector expressing very-low-density lipoprotein receptor. Mol Ther 2000, 2:256-61.
  15. Kitajima K, Marchadier DH, Burstein H, Rader DJ: Persistent liver expression of murine apoA-l using vectors based on adeno-associated viral vectors serotypes 5 and 1. Atherosclerosis 2006, 186:65-73.
  16. Sharifi BG, Wu K, Wang L, Ong JM, Zhou X, Shah PK: AAV serotype-dependent apolipoprotein A-I Milano gene expression. Atherosclerosis 2005, 181:261-9.
  17. Gao G, Vandenberghe LH, Wilson JM: New recombinant serotypes of AAV vectors. Curr Gene Ther 2005, 5:285-97.
  18. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM: Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 2002, 99:11854-9.
  19. Lebherz C, Gao G, Louboutin JP, Millar J, Rader D, Wilson JM: Gene therapy with novel adeno-associated virus vectors substantially diminishes atherosclerosis in a murine model of familial hypercholesterolemia. J Gene Med 2004, 6:663-72.
  20. Franceschini G, Calabresi L, Chiesa G, Parolini C, Sirtori CR, Canavesi M, Bernini F: Increased cholesterol efflux potential of sera from ApoA-IMilano carriers and transgenic mice. Arterioscler Thromb Vasc Biol 1999, 19:1257-62.
  21. Chiesa G, Stoltzfus LJ, Michelagnoli S, Bielicki JK, Santi M, Forte TM, Sirtori CR, Franceschini G, Rubin EM: Elevated triglycerides and low HDL cholesterol in transgenic mice expressing human apolipoprotein A-I(Milano). Atherosclerosis 1998, 136:139-46.
  22. Lewis GF: Determinants of plasma HDL concentrations and reverse cholesterol transport. Curr Opin Cardiol 2006, 21:345-52.