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Negative effects of smoke on novel HDL mimetic therapies

Institution: Lawrence Berkeley National Laboratory
Investigator(s): John Bielicki, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0082 Award: $657,970
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Exposure to cigarette smoke increases the risk for developing atherosclerosis, which is a common form of cardiovascular disease. Atherosclerosis is associated with a build-up of cholesterol in arteries, producing fatty plaques that restrict blood flow to the heart. The underlying mechanisms by which smoke promotes aortic cholesterol deposition and plaque formation are incompletely understood. However, clinical evidence suggests that oxidants in smoke alter lipoprotein metabolism and reduce the level of plasma HDL-cholesterol.

HDL is considered the “good” cholesterol, because it protects against atherosclerosis by mediating a process termed reverse cholesterol transport. In mediating reverse cholesterol transport, HDL removes excess cholesterol from the artery wall and then transports cholesterol to the liver for excretion in feces. This process is considered a major pathway for reducing fatty plaque build-up in coronary arteries. Consequently, cigarette smoke may impair an important protective mechanism that fights against the development of atherosclerosis.

Current clinical methods do not adequately assess the function of HDL in mediating reverse cholesterol transport. As a result, the impact of cigarette smoke on HDL activity has yet to be fully realized. Major unresolved issues relate to whether smoke exposure impairs responsiveness of the HDL system, which has relevance to disease development and the efficacy of therapeutic interventions. Our research seeks to create new biological tools to evaluate RCT responsiveness in vivo, i.e. in small laboratory animals and eventually humans. Specifically, we will develop and test a new class of synthetic bio-mimetic compounds based on HDL proteins that accelerate the RCT process. These bio-mimetics will be applied to studies of cigarette smoke to elucidate mechanisms of atherosclerosis development. Overall the studies are relevant to understanding the etiology of tobacco-related disease, creating novel compounds and approaches for the study, diagnosis and treatment of heart disease.

A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice.
Periodical: Journal of Lipid Research Index Medicus:
Authors: Bielicki JK, Zhang H, Cortez Y, Zheng Y, Narayanaswami V, Patel A, Johansson J, Azhar S ART
Yr: 2010 Vol: 51 Nbr: 20075422 Abs: Pg: 1496-1503

HDL Mimetic Peptide ATI-5261 Forms an Oligomeric Assembly in Solution That Dissociates to Monomers upon Dilution
Periodical: Biochemistry Index Medicus:
Authors: Zheng, Y., A. Patel , V. Narayanaswami, G. Hura, B. Hang, J.K. Bielicki ART
Yr: 2011 Vol: Nbr: 50 Abs: Pg: 4068-4076

The positional specificity of EXXK motifs within an amphipathic a-helix dictates preferential lysine_x000D_ modification by acrolein: implications for the design of high-density lipoprotein mimetic peptides
Periodical: Biochemistry Index Medicus:
Authors: Zheng, Y., S.H. Kim, A.B. Patel, V. Narayanaswami, A.T. Iavarone, G.L. Hura, and J.K. Biel ART
Yr: Vol: Nbr: Abs: Pg: PMID: 22800301