New Targets in Atherosclerosis
Tuesday, April 22, 2008
Presented by Biochemical Pharmacology Discussion Group and the American Chemical Society's New York Section
Organizer: Richard Ingraham, Boehringer Ingelheim Pharmaceuticals, Inc.
Atherosclerosis is a complicated disease with a relatively small number of cell types involved in lesion pathology. It has become apparent both from human and animal studies that more that just high LDL levels are involved in the disease process. It should be possible to target some of the inflammatory and other signaling pathways involved in atherosclerosis downstream from the stimuli which provoke it and alter or slow disease progression. Recent examples of potential new targets include members of the 5-lipoxygenase pathway which leads to inflammatory leukotrienes and the MAP kinase JNK2 which appears to alter the activities of scavenger receptors. Inhibition of either pathway seems to inhibit lesion progression. Another well known hypertension target, the angiotensin II pathway, now appears to be playing a seemingly independent role in promoting plaques formation as well as aneurysm. A greater understanding of this pathway may also provide us with new approaches to treat atherosclerosis.
The BPDG at the New York Academy of Sciences represents a diverse group of scientists and others with an interest in biochemistry, molecular biology, biomedical research, and related areas. Members are from pharmaceutical and biotechnology companies, and university and medical center research facilities across the Eastern United States. The group also serves as the Biochemical Topical Group for the American Chemical Society's New York Section. The purpose of the BPDG is to bring together diverse institutions and communities, industrial and academic, to share new and relevant information at the frontiers of research and development.
Current Approaches to Increase Reverse Cholesterol Transport
Richard Lawn, PhD, CV Therapeutics
Transcriptional Mechanisms in the Control of Vascular Inflammation and Atherosclerosis
Rajendra K. Tangirala, Ph.D, David Geffen School of Medicine at UCLA
The 5-Lipoxygenase/Leukotriene Pathway: Pro and Con Arguments as a Target in Atherosclerosis
Colin D. Funk, PhD, Queen's University
4:00 pm Inhibition of the Renin Angiotensin System Reduces Hypercholesterolemia-Induced Atherosclerosis
Alan Daugherty, PhD, University of Kentucky
Alan Daugherty, PhD; University of Kentucky
Infusion of angiotensin II into hypercholesterolemic mice greatly augments atherosclerosis through mechanisms independent of increased blood pressure. However, the endogenous renin angiotensin system is complex because of multiple bioactive peptides and receptors that can potentially promote or attenuate vascular pathology. Inhibition of responses to the endogenous renin angiotensin system have a profound effect on hyperlipidemia-induced atherosclerosis. In our own studies, deficiency of AT1a receptor subtypes greatly decreases atherosclerosis in LDL receptor -/- mice. Renin is the rate-limiting enzyme in synthesis of all angiotensin peptides. We have also recently demonstrated the effects of renin inhibition on atherosclerosis. To accomplish this, the novel renin inhibitor, aliskiren, was administered over a broad dose-range to fat-fed LDL receptor -/- mice. Renin inhibition resulted in striking reductions of lesion size in both the aortic arch