Atheroinflammatory Properties of LDL and HDL Particles Modified by Human Mast Cell Neutral Proteases
Year: 2018
Type: dissertation
Abstract: Atherosclerosis is a slowly progressing disease characterized by the development of inflamed fatty deposits called atherosclerotic lesions or plaques within the innermost layer of the arterial wall, the intima. First subclinical atheromatous changes within the arterial intima begin early in childhood as a response to cholesterol accumulation and serve as precursors for more advanced lesions that develop during the following decades through complex series of cellular events. During the degenerative process of lesion formation, the affected arteries gradually lose their normal structure and function, and may become narrowed by the growing plaques, a process leading to impeded blood flow to end-organ. Eventually multiple subclinical cellular events may result in the development of unstable, vulnerable plaques that are prone to rupture culminating in the life threatening clinical manifestation of myocardial infarction or ischemic stroke. Atherosclerosis is strongly associated with lifestyle and age. Enhanced plasma level of low-density lipoprotein (LDL) is considered a definitive risk factor of atherosclerosis, emphasizing the crucial role of LDL in the process of lesion development. Circulating LDL particles are the major carriers of cholesterol to the arterial intima and their retention by subendothelial proteoglycans and subsequent modification within the intima drives intramural cholesterol accumulation and ensuing formation of atherosclerotic lesions. Another lipoprotein playing a central, yet opposite role in atherogenesis is the high density lipoprotein (HDL). HDL and its principal protein component, apolipoprotein A (apoA)-I, act against atherosclerotic lesion development by removing cholesterol from the arterial wall and delivering it to liver for excretion. In addition to this process referred to as reverse cholesterol transport, HDL and apoA-I possess various anti-inflammatory properties by which they may hinder the inflammatory processes involved in the plaque development, and thus to protect from the disease progression. However, similar to LDL, HDL within the arterial intima is subjected to various structural and compositional modifications that impair its normal physiological function leading to generation of HDL particles with reduced antiatherogenic properties. LDL and HDL modifications within the arterial intima can be induced by extracellular enzymes released from cells present in the intima. MCs are tissue-dwelling effector cells of innate and adaptive immunity that differentiate from committed circulating progenitor cells and are present in increased numbers in atherosclerotic lesions. Being capable of releasing large amounts of various neutral proteases upon activation, MCs are potential source of LDL and HDL proteolyzing enzymes. The aim of this thesis was to investigate the ability of various human MC neutral proteases to cleave the protein moieties of LDL and HDL particles, apoB-100 and apoA-I, respectively and thus to contribute to the pathogenic processes of LDL accumulation and inflammation both essential in development of atherosclerotic lesions. In the present study, human MCs expressing four tryptase isoforms, chymase, carboxypeptidase A3, cathepsin G, and granzyme B is described. Of these, chymase and cathepsin G efficiently proteolyzed apoA-I and apoB-100, respectively generating C-terminally truncated apolipoproteins. Proteolysis by chymase resulted in reduced anti-inflammatory properties of apoA-I and impaired the ability of apoA-I to induce cholesterol efflux from macrophage foam cells. Furthermore, proteolysis of apoB-100 by cathepsin G induced formation of fused LDL particles with increased binding to human aortic proteoglycans and atherosclerotic lesions of human carotid arteries. Taken together, the data presented in this thesis propose novel mechanisms by which human MC neutral proteases may promote lipid accumulation and inflammation within the arterial wall and thus promote lesion development and progression. .
Source: Työväentutkimus Vuosikirja
Author: Katariina Maaninka
Institution: University of Helsinki
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2800443899