Project Description Narrative:
Cardiovascular disease (CVD) is the leading cause of death among Americans across all racial and ethnic groups. Importantly, it is the primary cause of death—surpassing all cancers combined—and accounted for over 31% of all deaths in the USA in 2019. In 2018, 12,053 people in Wisconsin alone died of CVD, representing 22% of deaths in the state. CVD is also a major economic burden to the people of Wisconsin. In 2005, the estimated annual direct and indirect costs for CVD-related care in Wisconsin were more than $7 billion. This economic strain, combined with mortality, clearly shows that more CVD research is absolutely required to reduce and reverse these alarming trends in our state and in the nation as a whole.
The most common type of CVD is atherosclerosis, an inflammatory disease characterized by the progressive accumulation of cholesterol within the arteries that leads to reduced blood flow and ultimately causes heart attacks. This process begins by the deposition of cholesterol from oxidized low-density lipoproteins (oxLDL) into macrophages, the critical cell type involved in the initiation of atherosclerotic lesion formation that results from cholesterol accumulation. Uncontrolled uptake of oxLDL-cholesterol leads to the formation of lipid filled macrophage foam cells, a hallmark of atherosclerosis that precedes plaque buildup in the arteries. Many of the pro-atherogenic effects of oxLDL are reversed or prevented by high density lipoprotein (HDL). Decades of epidemiological data strongly support a cardio-protective role for HDL, primarily due to its role in promoting net cholesterol flux from peripheral tissues to the liver for net excretion and whole-body cholesterol removal. Oddly enough, HDL-raising therapeutics and Mendelian randomization studies have shown that simply raising HDL-cholesterol (HDL-C) levels does not correlate with reduced cardiovascular events.
As such, assessing the function of HDL to better predict CVD risk is gaining credence. It is believed that systemic inflammation and/or oxidative stress can increase susceptibility of HDL particles to oxidative modifications that can dramatically promote dysfunction, often to the extent of causing HDL to become pro-atherogenic. Indeed, HDL can become oxidatively modified by a variety of compounds, including reactive aldehydes such as acrolein and malondialdehyde (MDA). In fact, the presence of acrolein or MDA adducts in arterial plaques and/or HDL strengthens the clinical and human relevance of the researchers’ studies. This project will test the overall hypothesis that modified forms of HDL promote pathways that lead to atherogenesis. The project team anticipates the outcomes of this study will help identify novel therapeutic strategies for preventing atherosclerosis.