Protein arginine methyltransferases as modulators of lipid metabolism and inflammation and the relevance for atherosclerosis

Zhang, Y. (2022)

Doctoral Thesis

Acute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from atherosclerosis, a progressive condition characterized by the accumulation of lipids, immune cells, and fibrous elements in large arteries. The pathogenesis of atherosclerosis involves complex interactions between a wide variety of cells, including monocytes, macrophages, neutrophils, and lymphocytes. It is essential to identify novel targets for therapeutic application in order to reduce the residual atherosclerotic cardiovascular disease risk in current and future patients. Recent studies have suggested that members of the protein arginine methyltransferase (PRMT) family can potentially serve as novel therapeutic targets for atherosclerosis because of their regulatory role in inflammation and metabolism. To validate the contribution of PRMTs in the progression of atherosclerosis, in the studies presented in this thesis we have investigated the effect of inhibition of PRMT functionality on atherosclerosis susceptibility in established atherosclerotic mouse models.To address the role of PRMTs in atherosclerosis, we therefore made use of specific PRMT inhibitors, i.e. TC-E 5003 for PRMT1 inhibition, TP-064 for PRMT4 inhibition, and GSK3326595 for PRMT5 inhibition, that thus far have primarily been applied in vivo in the context of cancer treatment.

• Atherosclerosis
• Cardiovascular diseases
• Lipid metabolism
• Protein arginine methyltransferase
• Macrophage
• Inflammation
• Mouse model

• All authors: Zhang, Y.
• Supervisor: Eck, M. van
• Co-supervisor: Hoekstra, M.
• Committee: Irth, H.; Bouwstra, J.A.; Willems van Dijk, J.A.P.; Wnag, Y.; Kersten, A.H.; Shiri-Sverdlov, R.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
• Date: 2022-12-15
• ISBN (print): 9789464691313
• Sponsorship: CSC