One of the major risk factors for atherosclerosis is hypercholesterolemia. The mechanisms linking hypercholesterolemia to atherosclerosis is largely unknown. In the present project we will study:
- The formation of atherogenic lipoproteins.
- The penetration and deposition of lipoproteins in arterial tissue.
- The lipoprotein-cellular interactions in atherosclerosis.
LDL is the main atherogenic lipoprotein. This project will further identify and characterize the assembly process of the atherogenic lipoproteins in the liver, and how the formation of these particles are regulated. The assembly process will be studied in cell culture, where the key enzyme diacylglycerol acyl transferase, DGAT, will be characterized and cloned. The importance of the apoB sequence for lipoprotein assembly will be analysed using truncated forms of apoB. In similar systems the requirements for the formation of Lp(a) will be studied.
The penetration and deposition of lipoproteins into the arterial tissue will be studied, in vivo in experimental atherosclerosis in rabbits and in vitro in tissue cultures. A focus will be put on the interaction between lipoproteins and the arterial proteoglycans, and the regulation av proteoglycan synthesis in the arterial wall. Proteoglycan synthesis will be studied in cell culture and in arterial tissue. The interaction with proteoglycans will be studied for different subfractions of LDL, as well as for Lp(a) and lipoproteins isolated from subjects with genetic hyperlipidemia.
Cell-lipoprotein interactions will be studied in macrophages and smooth muscle cells. Cells will be derived from arterial tissue or from cell lines in culture. In these studies mechanisms for lipoprotein modification will be analysed, especially lipoprotein oxidation and effects of vascular smooth muscle cell secretory phospholipase A2 (sPLA2) on lipoproteins. Furthermore effects of lipoproteins, native or modified, and products from sPLA2-hydrolyzed LDL (lysophospholipids and free fatty acids) on macrophage activation and smooth muscle cell proliferation will be studied.
To explore these central events in atherogenesis a network of research groups has been formed. Each group represents complementary knowledge or methodology that will be the basis for collaborative research and exchange. Thus creating a basis for the generation of new knowledge about atherogenesis.