sounds interesting..... anybody follow them??.......
J Lipid Res 2002 Jun;43(6):960-70
Identification of an IL-6 response element in the human LCAT promoter.
Feister HA, Auerbach BJ, Cole LA, Krause BR, Karathanasis SK.
Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI 48105. Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202. Esperion Therapeutics, Inc., Ann Arbor, MI 48108.
LCAT is a key enzyme of reverse cholesterol transport that is essential to maintain HDL-mediated lipid transport and cholesterol homeostasis. Alterations in LCAT expression have a profound effect on plasma HDL cholesterol concentrations. Previously LCAT mRNA and activity were shown to be regulated by several inflammatory cytokines, including the pleiotrophic cytokine interleukin-6 (IL-6). A series of full-length and sequential deletion LCAT promoter constructs were used to determine whether inflammatory stimuli affect LCAT transcription and to further identify functional, cytokine-responsive promoter regions that mediate this response. Using transfected HepG2 cells, results indicate that treatment with IL-6 induced a 2.5-fold activation of full-length LCAT promoter activity. A minimal (-1514 bp to -1508 bp) IL-6 response element with high sequence homology to the signal transducer and activator of transcription (STAT) family member, STAT3, was mapped within the distal promoter and shown to be sufficient to mediate the IL-6 response. Further, overexpression of STAT3 significantly enhanced the effect of IL-6 on LCAT promoter activity. These data suggest that the IL-6 responsive transcription factor, STAT3, contributes to LCAT transcriptional regulation. The elucidation of distinct biochemical signaling pathways associated with inflammation may provide new insight into transcriptional regulation of genes involved in lipid metabolism.
Circulation 2001 Jun 26;103(25):3047-50
High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization.
Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, Drake S, Cercek B.
Atherosclerosis Research Center, the Division of Cardiology, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif and Esperion Therapeutics Inc, Ann Arbor, Michigan, USA. shahp@cshs.org
BACKGROUND: Repeated doses of recombinant apolipoprotein A-I(Milano) phospholipid complex (apoA-I(m)) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I(m) could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice. METHODS AND RESULTS: High cholesterol-fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (n=16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; n=14), or 400 mg/kg of recombinant apoA-I(m) complexed with DPPC (1:2.7 weight ratio; n=18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux-promoting capacity was nearly 2-fold higher in recombinant apoA-I(m)-treated mice compared with saline and DPPC-treated mice (P<0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-I(m) injection, and it remained significantly elevated at 48 hours (P<0.01). Mice receiving recombinant apoA-I(m) had 40% to 50% lower lipid content (P<0.01) and 29% to 36% lower macrophage content (P<0.05) in their plaques compared with the saline- and DPPC-treated mice, respectively. CONCLUSIONS: A single high dose of recombinant apoA-I(m) rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype.
Esperion Begins Second Clinical Study of RLT Peptide (ETC-642) in Patients
Wednesday September 18, 11:34 am ET
ANN ARBOR, Mich., Sept. 18 /PRNewswire-FirstCall/ -- Esperion Therapeutics, Inc. (Nasdaq: ESPR - News), a biopharmaceutical company focused on discovering and developing HDL-targeted therapies, today announced the initiation of a second Phase I clinical study of its RLT Peptide product candidate (ETC-642) in patients with existing vascular disease. This study is designed to evaluate the safety and tolerability of ETC-642 at higher dose levels than those evaluated in the first clinical study.
This trial is a randomized, double-blind, placebo-controlled, dose- escalating study of up to twenty patients with stable atherosclerosis. In addition to safety and tolerability, the study will evaluate the pharmacokinetics and lipid effects of three dose levels of a single intravenous infusion of ETC-642. This trial will be conducted at Mayo Clinic. Mehmood A. Khan, MD, an endocrinologist and Director, Diabetes, Endocrine and Nutrition Clinical Trials Unit at the Mayo Clinic, will serve as the principal investigator of the study.
"We are pleased that the positive safety profile in the first clinical trial of ETC-642 has given us the opportunity to evaluate higher doses of ETC- 642 in this study," stated Roger S. Newton, Ph.D., President and CEO of Esperion. "With the data from this second study, we can design the protocol for a multiple dose study in patients for ETC-642."
ETC-642 mimics the biological properties of apolipoprotein A-I, the major protein in HDL, to promote cholesterol removal from arterial walls and other tissues and enhance reverse lipid transport. ETC-642 is a complex of peptide and phospholipids that mimics the functions of natural HDL and is being developed for the treatment of acute coronary disease. ETC-642 has been shown to increase HDL-cholesterol levels and to enhance cholesterol mobilization in preclinical studies and the first Phase I clinical study. Because of these properties, Esperion believes that the administration of ETC-642 may stimulate cholesterol removal in patients.
Esperion Therapeutics
Esperion Therapeutics, Inc. discovers and develops pharmaceutical products for the treatment of cardiovascular and metabolic diseases. Esperion intends to commercialize a novel class of drugs that focuses on a new treatment approach called "HDL Therapy," which is based on the Company's understanding of high-density lipoprotein, or HDL, function. HDL is the primary facilitator of the reverse lipid transport, or RLT, pathway by which excess cholesterol and other lipids are removed from arteries and other tissues and are transported to the liver for elimination from the body. Esperion's goal is to develop drugs that exploit the beneficial functions of HDL within the RLT pathway. Esperion currently has several product candidates under development for the treatment of cardiovascular and metabolic diseases. |
