The Influence of Hyperlipidemia on Endothelial Function of FPN1 Tek-Cre Mice and the Intervention Effect of Tetramethylpyrazine

Abstract

Background/Aims: Systemic iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including AS (Atherosclerosis). The hepcidin-ferroportin axis plays the key role in regulation of iron homeostasis and modulation of this signaling could be a potential therapeutic strategy in the treatment of these diseases. TMP (Tetramethylpyrazine) has been reported to have therapeutical effect on AS. Here, we aimed to investigate the effect of iron overload under hyperlipidemia condition on the endothelial injury, inflammation and oxidative stress by employing FPN1 Tek-cre mouse model with or without TMP intervention. Methods: Subjects for this study were 80 FPN1 Tek-cre mice and 40 C57BL/6 mice and we randomly divided them into six groups: Group N: C57BL/6 mice with normal diet, Group M: C57BL/6 mice with high-fat diet, Group FN: FPN1 Tek-cre mice with normal diet, Group FNT: FPN1 Tek-cre mice with normal diet and TMP injection, Group FM: FPN1 Tek-cre mice with high-fat diet, Group FMT: FPN1 Tek-cre mice with high-fat diet and TMP injection. After seven days of treatment, blood samples were obtained to detect the levels of blood lipids, Hepcidin, NO, ET-1, ROS, MDA, SOD, IL-1, IL-6 and TNF-α respectively. The liver and aorta were used for testing the lipid deposition by using hematoxylin and eosin(HE). Results: Hyperlipidemia could cause iron overload in the aorta and increased serum hepcidin level, particularly in FPN1 Tek-cre mice, and can be reversed by TMP intervention. Knockout of Fpn1 induced increase of serum hepcidin, exacerbated endothelial dysfunction, oxidative stress and inflammatory response, particularly under hyperlipidemia condition. TMP intervention attenuated these processes. Conclusions: Our study signifies the potential application of certain natural compounds to ameliorating iron disorders induced by hyperlipidemia and protecting on endothelial function through modulation of hepcidin-ferroportin signaling.

Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS

“…Inflammation is a significant contributor to ED at the arterial intima layer; monocytes release a number of inflammatory cytokines such as interkeukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF- α ), all of which may contribute to vascular endothelium injury [ 15 ]. TNF- α activates NADPH oxidase, which augments superoxide generation leading to a reduction in NO bioavailability [ 16 ].…”

Effect of tetramethylpyrazine and hyperlipidemia on hepcidin homeostasis in mice

“…TMP also been reported to improve clinical manifestations and liver function, which may be mediated by reduced expression of tissue factor via downregulated expression of the transcription factors, early growth response factor-1 and nuclear factor-κB p65 (30). In our previous study, TMP was shown to reverse the effect of iron deposition on endothelial functions and reduce IL-6 levels in hyperlipidemic FPN1 knockout mice (25). In the present study, the association between hyperlipidemia and serum hepcidin, and the effect of TMP were investigated.…”

“…disorder of iron metabolism is associated with various diseases, including iron-deficiency anemia and iron overload diseases, and the deregulation of hepcidin expression is also involved in these iron disorder diseases (15). It has been previously reported that hyperlipidemia can induce iron deposition in the aorta of mice (25). compared with the use of proteins and synthesized chemicals as drugs, natural compounds from traditional chinese medicinal plants have important properties, including abundant natural availability, high stability and low toxicity (26,27).…”

Efficacy and safety of tetramethylpyrazine phosphate on pulmonary hypertension: study protocol for a randomized controlled study

“…Given its anti-oxidative, anti-myocardial injury, and vasodilative effects [11][12][13][14], tetramethylpyrazine (TMP), a traditional Chinese herbal medicine, is widely used in the treatment of cardiovascular and cerebrovascular diseases [15][16][17][18]. The pathogenesis of PH involves oxidative stress, vascular inflammation, and imbalance of intracellular calcium homeostasis [19][20][21].…”