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Bone marrow transplantation in mice as a tool to study M2 macrophage activation in atherogenesis
Cardiovascular disease (CVD) due to atherosclerosis is a major cause of death. In atherosclerotic lesions, two major types of macrophages can be distinguished: 1) pro-inflammatory M1-macrophages, which promote atherosclerosis and 2) anti-inflammatory M2-macrophages, which are regarded athero-protective. Hence, skewing of macrophages from an M1 to an M2-phenotype might be a promising alternative therapeutic strategy against CVD. In this PhD dissertation, using the bone marrow transplantation (BMT) technique, we examined several genes that were hypothesized to be promising drug targets to favorably modulate macrophage phenotype and function, including the classic M2 marker gene Arginase 1 (Arg1), the key regulators of M2-macrophage activation Akt2 (AKT Serine/Threonine Kinase 2) and MKP2 (MAP Kinase Phosphatase 2), and Usf1 (upstream stimulatory factor 1). Although we were successful in skewing macrophages into an M2-phenotype, this...
Show moreCardiovascular disease (CVD) due to atherosclerosis is a major cause of death. In atherosclerotic lesions, two major types of macrophages can be distinguished: 1) pro-inflammatory M1-macrophages, which promote atherosclerosis and 2) anti-inflammatory M2-macrophages, which are regarded athero-protective. Hence, skewing of macrophages from an M1 to an M2-phenotype might be a promising alternative therapeutic strategy against CVD. In this PhD dissertation, using the bone marrow transplantation (BMT) technique, we examined several genes that were hypothesized to be promising drug targets to favorably modulate macrophage phenotype and function, including the classic M2 marker gene Arginase 1 (Arg1), the key regulators of M2-macrophage activation Akt2 (AKT Serine/Threonine Kinase 2) and MKP2 (MAP Kinase Phosphatase 2), and Usf1 (upstream stimulatory factor 1). Although we were successful in skewing macrophages into an M2-phenotype, this also led to accelerated foam cell formation, which counteracted the anti-inflammatory athero-protective effects of the M2-macrophage thereby limiting its therapeutic value. Overall this work underlines that modulation of macrophage polarization in atherosclerosis is feasible. However, more research is required to identify the key beneficial regulators and their overall effects in the complex microenvironment of atherosclerotic plaque before macrophage polarization can be exploited as an alternative therapeutic strategy against CVD.
Show less- All authors
- Ren, B.
- Supervisor
- Eck, M. van
- Committee
- Irth, H.; Bouwstra, J.A.; Willems van Dijk, J.A.P.; Biessen, E.A.L.; Winther, M.P.J. de
- Qualification
- Doctor (dr.)
- Awarding Institution
- Leiden Academic Centre for Drug Research (LACDR) , Science , Leiden University
- Date
- 2017-12-14
- ISBN
- 9789462998100
Funding
- Sponsorship
- China Scholarship Council CSC; CVON