Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Marlys Koschinsky

Abstract

Genetic studies have shown elevated plasma lipoprotein(a) (Lp(a)) levels to be an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease, however a definite mechanism for this pathogenicity has yet to be clearly identified. Oxidized phospholipids (oxPLs) have been implicated in facilitating atherogenic changes in the gene expression of vascular cells. As the primary carrier of oxPLs in the plasma, we hypothesize that Lp(a) contributes to vascular diseases by its enhanced ability to bind to and deliver oxPLs to tissue through a strong lysine binding site on its apolipoprotein(a) (apo(a)) component. Using a cultured primary coronary artery vascular smooth muscle cell (VSMC) model, we examined the effects of low-density lipoprotein (LDL), Lp(a) and apo(a) with or without this strong lysine binding site for OxPL addition on VSMC phenotype and viability. High concentrations of oxPLs were shown to induce atherogenic changes in VSMC gene expression and viability. However, likely due to inherent properties of our model, we were not able to show that physiologically relevant concentrations of Lp(a), apo(a) or LDL influenced VSMC gene expression. This study was the first to show that Lp(a) is capable of inducing expression of the apoptotic protein Bax in a cultured human coronary artery SMC model. This was not seen in cells treated with LDL, indicating that Lp(a) is uniquely cytotoxic to SMCs, likely due to its enhanced oxPL carrying capacity.

Summary for Lay Audience

Atherosclerosis begins when fats and cholesterol are deposited in the walls of the artery, causing an injury. This stimulates nearby cells to migrate to the injury site to help repair the wound. Smooth muscle cells (SMCs) are normally contractile cells that line your arteries and contribute to vascular tone. During atherosclerosis, they migrate to injury sites and begin secreting proteins such as collagen that build a fibrous layer around a developing lesion. Counter-intuitively, this growth of the plaque is protective. This is because plaques do not become problematic by gradually growing and occluding an artery, but rather cause harm when they rupture. Upon breaking, they send clots down your blood vessels where they can lodge themselves in your brain or heart, where they can cause strokes or heart attacks respectively. The collagen SMCs secrete can grow, but stabilize, the plaque. White blood cells are also recruited to growing lesions, where they begin to clear out deposited fats and cholesterol. However, they are often killed by ingesting too many chemically modified fats known as “oxidized” lipids. When white blood cells die in a lesion, they cause inflammation and contribute to the growth of a necrotic core of tissue in the plaque which can cause a rupture. Lipoprotein(a) (Lp(a))is the single most prevalent genetic risk factor for heart disease. Physically, it resembles low-density lipoprotein (LDL, or “bad” cholesterol) with one additional protein attached. Lp(a) is the major carrier of these damaging “oxidized” lipids in the plasma and can have serious effects on destabilizing atherosclerotic plaques. In this study we examine how Lp(a) and oxidized lipids can induce SMCs to change into white blood cell-type cells, simultaneously removing the protective collagen-producing cell type and replacing it with the inflammatory oxidized lipid-eating type.

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