This Article Full Text Full Text (PDF) All Versions of this Article: 118/7/743    most recent CIRCULATIONAHA.108.786822v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Merki, E. Articles by Tsimikas, S. Search for Related Content PubMed PubMed Citation Articles by Merki, E. Articles by Tsimikas, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL MALONALDEHYDE Related Collections Pathophysiology Risk Factors Lipid and lipoprotein metabolism Related Article

(Circulation. 2008;118:743-753.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice

Esther Merki, PhD; Mark J. Graham, BS; Adam E. Mullick, PhD; Elizabeth R. Miller, BS; Rosanne M. Crooke, PhD; Robert E. Pitas, PhD; Joseph L. Witztum, MD; Sotirios Tsimikas, MD

From the University of California San Diego, La Jolla (E.M., E.R.M., J.L.W., S.T.), Gladstone Institute of Cardiovascular Disease, San Francisco (R.E.P.), and Isis Pharmaceuticals, Inc, Carlsbad (M.J.G., A.E.M., R.M.C.), Calif.

Correspondence to Sotirios Tsimikas, Vascular Medicine Program, University of California San Diego, 9500 Gilman Dr, BSB 1080, La Jolla, CA 92093-0682. E-mail stsimikas{at}ucsd.edu

Received April 16, 2008; accepted June 11, 2008.

Background— Lipoprotein (a) [Lp(a)] is a genetic cardiovascular risk factor that preferentially binds oxidized phospholipids (OxPL) in plasma. There is a lack of therapeutic agents that reduce plasma Lp(a) levels.

Methods and Results— Transgenic mice overexpressing human apolipoprotein B-100 (h-apoB-100 [h-apoB mice]) or h-apoB-100 plus human apo(a) to generate genuine Lp(a) particles [Lp(a) mice] were treated with the antisense oligonucleotide mipomersen directed to h-apoB-100 mRNA or control antisense oligonucleotide for 11 weeks by intraperitoneal injection. Mice were then followed up for an additional 10 weeks off therapy. Lp(a) levels [apo(a) bound to apoB-100] and apo(a) levels ["free" apo(a) plus apo(a) bound to apoB-100] were measured by chemiluminescent enzyme-linked immunoassay and commercial assays, respectively. The content of OxPL on h-apoB-100 particles (OxPL/h-apoB) was measured by capturing h-apoB-100 in microtiter wells and detecting OxPL by antibody E06. As expected, mipomersen significantly reduced plasma h-apoB-100 levels in both groups of mice. In Lp(a) mice, mipomersen significantly reduced Lp(a) levels by 75% compared with baseline (P<0.0001) but had no effect on apo(a) levels or hepatic apo(a) mRNA expression. OxPL/h-apoB levels were much higher at baseline in Lp(a) mice compared with h-ApoB mice (P<0.0001) but decreased in a time-dependent fashion with mipomersen. There was no effect of the control antisense oligonucleotide on lipoprotein levels or oxidative parameters.

Conclusions— Mipomersen significantly reduced Lp(a) and OxPL/apoB levels in Lp(a) mice. The present study demonstrates that h-apoB-100 is a limiting factor in Lp(a) particle synthesis in this Lp(a) transgenic model. If applicable to humans, mipomersen may represent a novel therapeutic approach to reducing Lp(a) levels and their associated OxPL.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 118: 697-698. [Extract] [Full Text]

This article has been cited by other articles:

				R. Kato, C. Mori, K. Kitazato, S. Arata, T. Obama, M. Mori, K. Takahashi, T. Aiuchi, T. Takano, and H. Itabe Transient Increase in Plasma Oxidized LDL During the Progression of Atherosclerosis in Apolipoprotein E Knockout Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2009; 29(1): 33 - 39. [Abstract] [Full Text] [PDF]