We are entering an exciting new age in drug discovery and pharmacology. Biophysics, structural biology and physiology have all merged into a multi-discipline approach for developing and testing novel pharmaceutical agents. My laboratory investigates the mechanisms by which "4F," an apo A-I mimetic, decreases inflammation and improves vascular function. Apo A-I mimetics are small peptides that are designed to improve high-density lipoprotein (HDL) function. The apo A-I mimetic, 4F, exhibits powerful anti-inflammatory properties that we have shown improves vascular function in murine models of atherosclerosis, sickle cell disease, systemic sclerosis and asthma. Treatment of different murine models of vascular disease reveals that this small peptide increases vasodilation, promotes regression of existing lesions, inhibits influenza-induced macrophage infiltration of the vessel wall and inhibits inflammation surrounding brain microvessels which is hypothesized to improve cognitive function in hypercholesterolemic mice.
Recently we showed that D-4F restores vasodilation and inhibits vessel wall thickening in a murine model of hypercholesterolemia without lowering plasma cholesterol. In a murine model of sickle cell disease, we showed that D-4F improved vasodilation and limited the effects of ischemia/reperfusion injury of the liver. Such protection reduces the release of xanthine oxidase and actually helps protect vascular endothelial cells of the lung against increased oxidative stress. In an established murine model of scleroderma we showed that D-4F inhibited the formation of angiostatin in the hearts of the mice. Such changes correlated with marked increases in VEGF-stimulated angiogenesis and, in flow and endothelium- and eNOS-dependent vasodilation. Finally, we have used D-4F to decrease airway inflammation and improve airway reactivity in a murine model of asthma. The fact that this small peptide is able to decrease inflammation and improve vascular and pulmonary function in such diverse disease states suggests that it is targeting a mechanism that is likely fundamental to all forms of vascular disease.
My laboratory investigates mechanisms of vascular function with respect to the cell biology of endothelial nitric oxide synthase (eNOS). Our goal is to understand and define the cellular mechanisms governing nitric oxide and superoxide anion from eNOS itself. We use several transgenic and gene knock-out mice as murine models of disease and to test specific mechanisms impairing vasodilation. On the basis that D-4F rearranges HDL to isolate and remove lipid hydroperoxides from the HDL particle, we think that proinflammatory lipids generated during disease play critical roles in inhibiting vascular function; and, that these proinflammatory lipids, in turn, accelerate and enhance the disease process. Although we do not know exactly how D-4F and other apo A-1 mimetics work, we hypothesis that they restore vascular function in at least two ways; 1) by directly interacting with the vessel wall and 2) indirectly by improving HDL function, which, in turn, improves vascular health by decreasing inflammation of the vessel wall. Accordingly, one of the goals of my laboratory is determine if, and the extent to which, D-4F and other apo A-1 mimetics improve vascular function by these two distinct mechanisms.
My laboratory is pursuing these hypotheses in murine models of hypercholesterolemia, sickle cell disease, systemic sclerosis and asthma. As oxidative stress is well know to impair HDL function, targeting HDL may be an important new avenue for treating autoimmunity, rheumatoid arthritis, pulmonary disease, as well as sickle cell disease, hypercholesterolemia, systemic sclerosis and asthma. We are seeking active collaborations with physicians who treat children and adult patients with these diseases. It is our hope to establish a strong basic science program in each disease state. From there upon which we will be able to build translational programs to treat vascular disease in humans. The possibilities for apo A-1 mimetics to improve vascular function appear to be endless at this point.