Triglyceride-Rich Lipoproteins and Abdominal Aortic Aneurysm Growth and Progression

ABSTRACT Abdominal aortic aneurysm (AAA) is a life-threatening condition in which progressive dilatation of the abdominal aorta leads to rupture. Our recent findings from a comprehensive genome-wide association study (GWAS) suggest that triglyceride-rich lipoproteins (TRL) are a potential key mediator of AAA. TRL enter circulation from an endogenous pathway via the liver as very low-density lipoprotein (VLDL) and from an exogenous pathway via the intestine as chylomicrons. In plasma, TRL undergo rapid catabolism by lipases into remnant particles that are proposed to promote atherosclerosis and inflammation. Human genetic and animal studies have implicated lipoprotein lipase (LPL) and its regulators as key determinants of circulating TRL levels. Our published and preliminary data further support the involvement of TRL in AAA pathobiology: (1) genetic causal inference experiments prioritizing TRL containing non-high-density lipoprotein cholesterol (nonHDL-c) over low-density lipoprotein cholesterol (LDL-c) as the most likely major causal lipid fraction promoting AAA; (2) a genome-wide significant association between a missense variant in LPL associated with increased TRL and AAA risk; (3) data from Mendelian randomization experiments implying a causal relationship between increased plasma apolipoprotein A5 (ApoA5) levels (a key regulator of LPL and circulating TRL) and decreased AAA risk; (4) elevated TRL in angiotensin II (AngII)-infused mice augments the development, growth, and rupture of AAA. Despite the robust evidence, significant knowledge gaps persist: The effect of TRL-targeted therapies on AAA remains unexplored. Positioning emerging TRL-targeted therapies to prevent and attenuate expansion of AAA requires definitive causal evidence of their role in not only development but also growth. Also, the causal role of TRL in AAA development and growth has not been defined. Furthermore, mechanistic data linking TRL to AAA development or growth is non-existent. These key knowledge gaps temper enthusiasm for the large-scale efficacy trials that will be necessary to position emerging TRL-targeted therapies to treat AAA. To elaborate data and build evidence to support clinical efficacy trials, we will test the central hypothesis that TRL concentration and composition contribute to both AAA growth and progression in humans and AAA mouse models. Aim 1 will quantify the relationship of TRL concentrations and composition with AAA development and growth using human genetics approaches to causal inference. Aim 2 will determine the therapeutic potentials of established AAAs and explore mechanistic links between elevated TRL and AAA growth and progression using two classic mouse AAA models. This application draws upon a strong collaborative team encompassing expertise in human genetics (Drs. Damrauer and Levin), lipoprotein biology (Dr. Temel), and mouse AAA models (Drs Lu, Daugherty, and Tsao). We expect that the proposed project will provide new translational insights into non-interventional medical therapies of AAA in patients.