Reconstituted HDL Elicits Marked Changes in Plasma Lipids Following Single-Dose Injection in C57Bl/6 Mice

Journal of Cardiovascular Pharmacology and Therapeutics - Tập 17 Số 3 - Trang 315-323 - 2012
Zhu Chen1, Edward A. O’Neill1, Roger Meurer1, Karen Gagen1, Silvi Luell1, Shengping Wang1, Marina Ichetovkin1, Betsy Frantz-Wattley1, Suzanne S. Eveland1, Alison M. Strack1, Timothy S. Fisher1, Douglas G. Johns1, Carl P. Sparrow1, Samuel D. Wright2, Brian K. Hubbard1, Ester Carballo‐Jane1
1Cardiovascular Diseases, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA
2CSL Limited, Parkville, Victoria, Australia

Tóm tắt

High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-β HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.

Từ khóa


Tài liệu tham khảo

10.1161/01.CIR.74.6.1217

10.1016/0021-9150(95)05675-0

10.1097/HCO.0b013e3283410c16

10.1161/CIRCULATIONAHA.108.772665

10.1016/j.jacc.2010.02.035

10.1194/jlr.M900151-JLR200

10.1161/01.CIR.0000134275.90823.87

10.1194/jlr.M800539-JLR200

10.1161/ATVBAHA.109.187518

10.1016/j.bmc.2010.09.074

10.1161/01.ATV.19.4.979

10.1016/j.jacc.2008.12.008

10.1001/jama.297.15.jpc70004

10.1161/CIRCRESAHA.108.182063

10.1016/0005-2760(92)90049-2

10.3858/emm.2009.41.6.047

10.1016/j.jacc.2010.11.015

10.1194/jlr.M700138-JLR200

10.1194/jlr.M011098

10.1161/01.CIR.100.6.594

10.1016/S0022-2275(20)32212-4

10.1074/jbc.M010230200

10.1046/j.1423-0410.1996.7130155.x

10.1161/01.ATV.0000089328.23279.3F

10.1007/s00125-008-0975-2

10.1194/jlr.M500187-JLR200

10.1016/S0022-2275(20)32370-1

10.1194/jlr.M700506-JLR200

10.1093/clinchem/42.12.1992

10.1194/jlr.M300231-JLR200

10.1172/JCI118180

10.1007/BF02536066

10.1016/S0022-2275(20)41500-7

10.1016/S0021-9673(01)88871-3

10.1016/S0006-291X(81)80091-5

10.1161/01.ATV.16.9.1203

Thông tin
Thông tin xuất bản

Journal of Cardiovascular Pharmacology and Therapeutics

Tập 17 Số 3

315-323

Thông tin tác giả