Lipoprotein(a) in cardiovascular disease

Sammanfattning: The atherosclerotic process is continuous and starts early in life. Risk factors for atherosclerosis include hyperlipidemia, hypertension, smoking and diabetes mellitus. Fatty streaks characterised by lipid-laden macrophages are early signs of atherosclerosis. Binding of LowDensityLipoproteins(LDL) to proteoglycans is believed to be one of the first steps in atherosclerosis. After many years the plaques are more complex with aggregations of lipids, extracellular matrix, and necrotic cells with variable content of inflammatory cells. The etiology of atherosclerosis is complex and multifactorial. Several new risk factors have been studied recently. On such factor may be lipoprotein(a)(Lp(a)). Lp(a) has been associated to cardiovascular disease in several studies. Lp(a) is an LDL-like particle with an apolipoprotein(a) part attached to apoB by a disulfide bridge.The regulation of serum levels of Lp(a) has been studied in this thesis. It has earlier been shown that Growth Hormone increases the levels of Lp(a). It has been speculated that this effect could be mediated by Insulin-like Growth Factor-1(IGF-1). Effects of IGF-1 treatment were tested in the present study during a two weeks period. The results demonstrate that IGF-1 treatment resulted in decreased levels of Lp(a)(-18.5%). Lowered levels of cholesterol and triglycerides were also seen. We also studied the effects of N-acetylcysteine treatment. No effect of N-acetylcysteine treatment on Lp(a) was seen during treatment. There was a reduction of homocysteine, cysteinylglycine and glycine as a response to the treatment. The interactions of Lp(a) and LDL with extracellular matrix have been investigated. In studies with human arterial smooth muscle cell derived extracellular matrix we saw an increased binding of 125I-LDL in the presence of Lp(a). This binding was reduced after treatment of the matrix with chondroitinase ABC, implying an involvement of proteoglycans in the interaction. In addition the interaction of 125I-LDL with matrix was stronger in the presence of Lp(a). In a population with coronary heart disease (n=964) Lp(a)levels and apo(a) isoforms was studied as a prognostic factor during a twelve years follow-up.A total of 363 patients died during follow-up. The smallest isoform of apo(a) was associated with a two-fold increase in risk. High levels of lipoprotein(a) were not associated with increased risk. In women, but not in men the risk decreased with increasing molecular weight of the apo(a) isoforms. These results support the endocrine regulation of serum Lp(a) levels, specifically a reduction by IGF-1 was seen. Lp(a) increases the binding of LDL to human arterial smooth muscle cell derived extracellular matrix in vitro. More LDL particles are bound in the presence of Lp(a) and the interaction is stronger. Apo(a) isoforms but not Lp(a) levels were found to be risk factors in patients with CHD, especially among women. These findings emphasize the importance of a gender-specific analysis of risk factors for CHD.

  Denna avhandling är EVENTUELLT nedladdningsbar som PDF. Kolla denna länk för att se om den går att ladda ner.