The contribution of BMP-Hepcidin-Ferroportin-Iron signaling to atherogenesis

• Applicant: Dr. Florian Wunderer
• Subject Area: Anaesthesiology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 312916848

Atherosclerosis is a chronic disease and the leading cause of death and loss of productive life-years in industrialized societies. Research has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation, including processes such as lipoprotein oxidation, inflammation and immunity. Yet, despite these advances, additional, effective strategies are needed to treat and prevent the consequences of atherogenesis, including myocardial infarction and stroke. Hepcidin is the master regulator of body iron homeostasis. Hepcidin targets ferroportin (FPN) for degradation, thereby reducing export of iron from enterocytes, hepatocytes and macrophages. Inflammatory mediators, such as IL-6, increase hepcidin production, and thereby reduce iron availability for erythropoiesis leading to anemia of inflammation. The BMP-hepcidin-FPN signaling pathway also appears to contribute to inflammatory processes not typically attributed to abnormalities of iron homeostasis, including atherosclerosis. Hepcidin-FPN-mediated macrophage polarization may play a crucial role in atherogenesis. In this grant application, we propose to use genetic- and molecular-biological techniques to study iron homeostasis, with a new focus on the role of hepcidin-FPN signaling in macrophage function and the role of this signaling pathway in atherogenesis. We hypothesize that hepcidin-induced degradation of FPN contributes to atherogenesis by inducing a pro-inflammatory macrophage phenotype and that inhibition of BMP signaling attenuates atherogenesis by down-regulating hepcidin expression. Therefore the objective of this proposal is to characterize the contribution of BMP-hepcidin-FPN-iron signaling to atherogenesis. Complementary genetic and pharmacological approaches to modulate hepcidin and FPN expression in the context of LDL receptor deficiency are planned to elucidate the regulation of macrophage function by hepcidin-FPN-iron signaling and the contribution of the signaling pathway to atherogenesis in different mouse models. The hosting laboratory has broad expertise in molecular and cellular biology as well as murine models of atherogenesis. The Bloch laboratory was involved in many of the initial studies on BMP and hepcidin. The team's accomplishments include discovery of the first small molecule inhibitors of BMP signaling and demonstration that these inhibitors can be used to treat anemia of inflammation. Therefore, the techniques included in this proposal are already well established on site. The proposed research program will provide important insights into the role of hepcidin-FPN-iron signaling in macrophage function and atherosclerosis. The observation that BMP-hepcidin-FPN signaling regulates vascular macrophage accumulation and atherogenesis provides a new area for therapeutic interventions including potentially the use of BMP inhibitors to treat patients with atherosclerotic cardiovascular disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Dr. Donald Bloch; Professor Dr. Warren Myron Zapol