Triglyceride-rich lipoproteins and abdominal aortic aneurysm growth and progression

Abdominal aortic aneurysm (AAA) is a life-threatening condition in which aneurysm growth through progressive dilatation of the abdominal aorta leads to rupture. The only efficacious therapy to prevent or treat rupture is open or endovascular surgical repair. Non-surgical therapies are desperately needed to prevent aneurysm growth and protect from rupture, while averting the need for operative repair. Our recent findings from a comprehensive genome-wide association study (GWAS) suggest that triglyceride- rich lipoproteins (TRL) are a 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. Because of this, numerous TRL-targeted therapies are in clinical development. Our published and preliminary data support the involvement of TRL in AAA pathobiology including: (1) human genetic experiments implicating non-high-density lipoprotein cholesterol (nonHDL-c) over low-density lipoprotein cholesterol (LDL-c) as the likely causal lipid fraction; (2) a genome-wide significant association between a missense variant in lipoprotein lipase which increases TRL and AAA risk; (3) genetic data implying a causal relationship between apolipoprotein A5 (ApoA5) levels (a regulator of circulating TRL) and AAA risk; (4) elevated TRL in angiotensin II (AngII)-infused mice augmenting the development, growth, and rupture of AAA. Despite the robust evidence, significant knowledge gaps persist: positioning emerging TRL-targeted therapies as a non-surgical treatment of AAA requires definitive causal evidence of their role in AAA growth and progression rather than merely susceptibility. Furthermore, mechanistic data linking TRL to AAA growth and progression 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 build evidence to support clinical efficacy trials, we will test the central hypothesis that TRL concentration and composition contribute to both AAA susceptibility/development and growth and progression in humans and multiple AAA mouse models. Aim 1 will quantify the relationship of TRL concentrations and composition with AAA growth and progression using human genetics approaches. Aim 2 will determine the mechanistic link between elevated TRL and AAA growth and progression using 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 understanding the causative associations between TRL and AAA growth and progression and yield viable targets for non-surgical therapy of AAA. Project Number: 1R01HL181587-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Scott Damrauer (+2 co-PIs) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $713,382 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IVBH-H (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18158701