The role of Resolvin D1 and the G protein-coupled receptor 32 in Atherosclerosis

• Applicant: Dr. Silke Thul
• Subject Area: Cardiology, Angiology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267665186

Atherosclerosis and subsequent cardiovascular diseases like myocardial infarct or stroke represent a rising cause of death worldwide. The pathogenesis of atherosclerosis is associated with chronic inflammation, in which numerous immune cells and mediators are involved. In the process, next to pro-inflammatory acting lipid mediators like leukotrienes, the contribution of anti-inflammatory, pro-resolving lipid mediators such as Resolvins, Protectins or Maresins was recently discovered. Resolvin D1 is synthesized by lipoxygenases from the omega-3 fatty acid docosahexaenoic acid and promotes the resolution of inflammation by inhibition of inflammatory leukocyte recruitment and by facilitation of phagocytosis of apoptotic cells by macrophages. There is evidence that deficiencies in the pro-resolving phase of inflammation lead to chronic inflammation and associated diseases such as atherosclerosis, arthritis or Alzheimer´s disease. The potent anti-inflammatory and pro-resolving properties regarding cell migration, phagocytosis and cytokine expression make Resolvin D1 a promising candidate for a therapy to support resolution of chronic inflammation. The aim of this proposal is the systematic investigation of a role of Resolvin D1 signal transduction through its associated G-protein coupled receptor GPR32 in the development of atherosclerosis in vitro and in vivo. By using the analysis of cell migration as a read-out system, effects on macrophages and vascular smooth muscle cells that are relevant in atherosclerosis will be studied in three experimental parts: First, I will evaluate how Resolvin D 1 signaling through GPR32 influences cell migration and phagocytosis of apoptotic cells (effercytosis) by establishing an in vitro test system based on cell culture.Subsequently, the influence of GPR32-dependent signal transduction on disease outcome will be assessed in vivo on the histological and cellular level. Analysis will include mice overexpressing the human GPR32 in a mouse model for atherosclerosis (ApoE knockout) as well as in parallel human atherosclerotic tissue obtained from the clinic. In summary, the role of Resolvin D1 and its receptor GPR32 in atherosclerosis has not been described adequately. The obtained results will provide new insights into the molecular events that are crucial during the resolution of inflammation. Importantly, the outcome of this research might further lead to a new molecular target for a therapeutic strategy in atherosclerosis and possibly other diseases associated with chronic inflammation.

• DFG Programme: Research Fellowships
• International Connection: Sweden
• Host: Professor Dr. Magnus Bäck