Apolipoprotein A-IV and its role in coronary artery disease

Research project P 14717 ApolipoproteinA-IV and its role in coronary artery disease Florian KRONENBERG 09.10.2000 There is rising evidence that apolipoprotein A-IV (apoA-IV) plays an anti-atherogenic role: first, it participates in several steps of the reverse cholesterol transport pathway, which removes cholesterol from peripheral cells and transports it to the liver and steroidogenic organs where cholesterol can be metabolized. Second, an endogenous antioxidative capability was demonstrated recently. Third, fat-fed mice that overexpress either human or mouse apoA-IV demonstrated a significant reduction of aortic atherosclerotic lesions compared to control mice. Fourth, we recently demonstrated for the first time that low apoA-IV plasma concentrations are strongly associated with coronary artery disease (CAD) in humans. Therefore, we will study apoA-IV and its role in atherosclerosis by the following projects: 1. In a first step, we will investigate which variables have an influence on apoA-IV plasma concentrations. It is a prerequisite for further epidemiological studies to know potential confounders of apoA-IV in more detail for consideration in future studies. Since the Bruneck Study represents an ideal setting of a population-based study including many biochemical variables and intensively recorded variables of diet and lifestyle, it will be possible to find potential confounders of apoA-11V concentrations and to define the magnitude of confounding. Knowing these confounders will give hints concerning the regulation of apoA-IV plasma concentrations. The results of this question will be the basis for all other projects (e.g. for segregation and linkage analysis apoA-IV levels have to be adjusted for confounders). 2. Clinical epidemiological studies will address the significance of apoA-1V as risk factor/marker for atherosclerosis and atherogenesis. It will, be mandatory to investigate in prospective studies whether low apoA-IV levels are only an epiphenomenon of atherosclerosis (but nevertheless an interesting screening tool) or whether they are related to the development and progression of atherosclerosis. 3. We will investigate the distribution of apoA-IV and especially the amount of non-HDL-associated apoA-IV in plasma of patients with CAD compared to controls. This question is of importance due to recent in vitro studies suggesting that apoA-1V unassociated with HDL is responsible for an enhanced cholesterol efflux from J774 macrophages which indicates that non-HDL-associated apoA-IV might have a significant impact on cellular cholesterol release. 4. Functional studies will determine whether apoA-1V and the various plasma fractions of apoA-IV from CAD patients results in a different cholesterol efflux when compared to apoA-IV from controls. By adding apoA-IV in excess, we will investigate whether an increase of apoA-IV would be beneficial for cholesterol efflux. Results, of this study will indicate whether a pharmacological increase of apoA-1V might represent a new therapeutical approach. 5. Genetic epidemiological studies will be applied to study the genetic determination of apoA-IV plasma levels. Segregation analysis in large Utah pedigrees will be done to improve the power of subsequent parametric linkage analysis. The genome-wide linkage analyses will be performed using approximately 600 markers which are already typed in 1916 subjects of these families. Using these approaches we will gain information about genetic and non-genetic determinants of apoA-IV concentrations, the clinical epidemiological association between apoA-IV and atherosclerosis and functional aspects of apoA-IV in atherogenesis.

Human apolipoprotein A-IV (apoA IV) is a protein which was suggested to protect against atherosclerotic events. In vitro studies showed that apoA IV is involved in the transport of cholesterol to liver cells where it is taken up, degraded or used for important metabolic pathways. Another potentially anti-atherogenic effect of apoA IV is its endogenous antioxidative capability. We recently demonstrated for the first time that low apoA IV plasma concentrations are associated with coronary artery disease in humans. We intended to investigate in this 15-month project two major questions: 1. Which variables have a major influence on apoA-IV plasma concentrations. This is a prerequisite for further epidemiological studies. We identified renal function as one of the major confounder variables of apoA-IV levels. In a cohort of patients with renal disease, we observed that apoA-IV is a very early marker of renal impairment. 2. A more detailed investigation of the association of low apoA-IV plasma levels with atherosclerotic complications. We observed lower apoA IV concentrations in renal patients who had already suffered from an atherosclerotic event when compared to those without an event. The investigation of an influence of apoA-IV on carotid atherosclerosis in the large population-based Bruneck Study is still in progress. We also investigated whether a different distribution of apoA-IV in plasma of coronary artery disease patients compared to controls can explain the association with coronary artery disease. We observed no significant differences in the pattern of these fractions between patients and controls. Therefore, the anti-atherogenic effect of apoA-IV has to be explained by other properties of apoA-IV. Further, mainly prospective studies are necessary to investigate the association and a possible causality of apoA-IV with atherosclerotic complications.