hepcidin-ferroportin axis is the key signaling mechanism that controls systemic iron homeostasis. Increased serum hepcidin is associated with multiple types of cancer and atherosclerosis

Iron homeostasis is strictly regulated in mammals, and disordered iron metabolism is recognized as a risk factor for various diseases, including cardiovascular disease. The hepcidin-ferroportin axis is the key signaling mechanism that controls systemic iron homeostasis. Increased serum hepcidin is associated with multiple types of cancer and atherosclerosis (AS), and therapeutics that decrease hepcidin levels have been proposed to treat these diseases. However, the effects of abnormal circulating hepcidin on hyperlipidemia remain unexploited. The natural compound tetramethylpyrazine (TMP) has been reported to have therapeutic effects on cardiovascular diseases, whereas the mechanisms involved remain incompletely understood. Thus, the effects of TMP on the expression of hepcidin in hyperlipidemic mice were investigated and the mechanisms involved were explored. Hyperlipidemia increased serum hepcidin, which was inhibited by TMP intervention. The results also indicated that TMP may decrease hepcidin expression via inhibition of Stat3 signaling. These findings suggest a promising rationale to prevent and hyperlidemia by targeting hepcidin or its upstream regulators, and highlight the potential application of natural compounds in treating hepcidin disorder-associated diseases. Introduction Iron homeostasis is tightly regulated under normal settings, where the hepcidin-ferroportin axis is fundamentally responsible for the regulation of iron supply, utilization, recycling and storage. Hepcidin, a peptide hormone, is prominently synthesized by the liver and secreted into serum followed by tissue localization through circulation (1). Hepcidin inhibits iron absorption from the duodenum, and iron export from macrophages and hepatocytes is reduced by via its hepcidin-induced degradation of iron exporter ferroportin (FPN) (2). The expression of hepcidin is regulated by multiple signals directly or indirectly, including iron levels, anemia, hypoxia, inflammation, pathological conditions and cytokines, and changes in hepcidin expression are associated with various diseases (3). deregulated hepcidin-FPN signaling is implicated iron-associated diseases, such as hereditary hemochromatosis and anemia of inflammation (4‐6), and also in atherosclerosis (AS) (7-9). AS is a chronic vascular disease and it is the pathological basis of various cardiovascular pathologies. There are different theories regarding the pathogenesis of AS, including lipid infiltration theory (10). With increasing studies on the metabolism of AS, the role of iron in the progression of AS has been established (11). A previous study reported that high expression of hepcidin in AS plaques can increase the iron deposition in macrophages and promote the instability of plaques (4). Tetramethylpyrazine (TMP), a natural compound extracted from the chinese herb chuanxiong rhizome (12), has been reported to have an anti-AS effect by inhibiting aggregation of platelet, proliferation of smooth muscle cells and reduced lipid peroxidation and protecting endothelial cell function (12,13). Thus, in the current study, the potential effect of TMP on hepcidin expression was investigated. At present, two signaling pathways are recognized to predominantly control hepcidin expression under normal conditions, hemojuvelin (HJV)-bone morphogenetic proteins (BMPs)/Smad and Janus kinase (JAK)/signal transducer and activator of transcription (Stat) signaling pathways (14,15). BMPs are a class of multifunctional transforming growth factors, which have an important role in cell proliferation, differentiation, apoptosis and tissue development (16). Among Effect of tetramethylpyrazine and hyperlipidemia on hepcidin homeostasis in mice MIAO ZHANG1,2*, MING-YUE SUN2*, cHUN-YU GUO2, JING‐SHANG WANG2, FENG-QIN XU2 and HUI-JUN YIN2,3 1Graduate School, Beijing University of chinese Medicine, Beijing 100029; 2department of cardiovascular disease, Xiyuan Hospital, china Academy of chinese Medical Sciences, Beijing 100091; 3Graduate School, Gansu University of chinese Medicine, Lanzhou, Gansu 730000, P.R. china Received January 4, 2018; Accepted September 27, 2018 dOI: 10.3892/ijmm.2018. 3968 Correspondence to: Professor Feng-Qin Xu or Professor Hui-Jun Yin, department of cardiovascular disease, Xiyuan Hospital, china Academy of chinese Medical Sciences, Building Xingyuan, 1 Xiyuan caochang, Beijing 100091, P.R. china E-mail: doctorxu@aliyun.com E-mail: huijunyin@aliyun.com *contributed equally Abbreviations: FPN, ferroportin; AS, atherosclerosis; TMP, tetramethylpyrazine; Tc, total cholesterol; TG, triglycerides; BMP, bone morphogenetic protein; IL-6, interleukin-6; HJV, hemojuvelin; HH, hereditary hemochromatosis; H&E, hematoxylin and eosin