Grant: Project Grant

Abdominal aortic aneurysm (AAA), the localized enlargement of the abdominal aorta, is a disease of the abdominal aorta wall and currently has no medical treatment. Surgical repair is the only option available to date. The leading cause of AAA is the malfunction of aortic smooth muscle cells (SMCs), the primary cell component in the aortic wall. Normal SMCs can contract and participate in the regulation of blood pressure. When they lose contractility or malfunction, the presence of blood pressure will push the local artery wall out to form aneurysms. PCSK9 (proprotein convertase subtilisin/kexin type 9) increases blood lipids and accelerates cardiovascular disease. We found that PCSK9 is also present in SMCs of AAA in humans. Our pilot studies showed that PCSK9 induces several changes, such as loss of contractility and death of human aortic SMCs, and increases the levels of several enzymes responsible for breaking the aortic structure, which is novel. We also found that PCSK9 degrades the low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) and LRP8, two proteins on the cell surface that bind to PCSK9, in human aortic SMCs. Breakdown of either LRP1 or LRP8 induces disease of the blood vessel, including AAA and atherosclerosis. Thus, we speculate that PCSK9 in aortic SMCs has a vital role in the development of AAA. To test this possibility, we will experimentally remove PCSK9 from SMCs and investigate if AAA still occurs in mice. We will also study how PCSK9 induces cell death of SMCs and increases enzyme levels for tissue breakdown. Our research is to discover a novel role for PCSK9 and define PCSK9 as a therapeutic target for developing an approach to prevent progression and rupture of AAA.