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Vaspin Signaling Pathway

Figure1. Vaspin signaling pathway.

An overview of vaspin Adipose tissue is an energy storage organ and an important endocrine organ of the whole body. Adipose tissue mainly includes subcutaneous adipose tissue and visceral adipose tissue (VAT), which are not only involved in energy metabolism, but also have more active endocrine functions in secreting a wide variety of fat factors such as leptin, adiponectin, resistin and lactone. Vaspin (visceral adipose tissue-derived serine protease inhibitor) is a newly discovered adipokine in recent years. It transmits signals through vaspin and the above adipokines, adipose tissue and other tissues, and participates in the pathological and physiological processes of glycolipid metabolism, blood pressure, obesity, and apoptosis, for example, inflammatory reaction can affect the development of diabetes and atherosclerosis through multiple links. Therefore, the study of vaspin signaling pathway is particularly important for the treatment of related diseases.

Vaspin family

Vaspin is a member of the serine protease inhibitor family. When an animal model of spontaneous type 2 diabetes was established in OLETF (Otsu-ka Long-Evans Tokushima Fatty) rats, and the peak plasma concentration of obesity and insulin occurred, Hida et al found that vaspin was highly expressed in visceral adipose tissue. It was found to be a novel gene, ol-64, which shares 40% homology with α1-antitrypsin. Studies have shown that vaspin is not only expressed in adipose tissue, but also expressed in different degrees in tissues such as skin, stomach, pancreas, liver and hypothalamus, suggesting that vaspin may exert its physiological effects on multiple target organs. The open reading frame of vaspin cDNA consists of 1245, 1236, and 1242 deoxynucleotides in human, rat, and mouse, respectively. The proteins contain 415, 412, and 414 amino acid residues, respectively. The human vaspin protein is a single peptide with a hydrophobic N-terminus with a relative molecular mass of 45200. Heiker et al. found that its crystal structure has the typical structural characteristics of the serpin family, namely, one reaction center ring, three β-sheets and nine α - spiral composition. Hida et al found that vaspin mRNA was expressed in visceral adipose tissue in OLETF rats and was specifically expressed in visceral white adipose tissue. It was also found to be less or not expressed in brown adipose tissue and other non-adipose tissues of human, rat and mouse. Kloting et al found that vaspin mRNA is only expressed in visceral adipose tissue and subcutaneous fat in overweight or obese patients, but not in non-obese patients. In contrast, Fain et al found that vaspin mRNA is mainly expressed in non-adipocytes. In other literature, vaspin is expressed in different degrees in tissues such as human stomach, pancreas, liver and C57BL/6 hypothalamus. In summary, the expression of vaspin is widely distributed, but the tissue specificity of its expression is still controversial. Since vaspin is a newly discovered adipokine in the past decade, its research is still in its infancy, and more studies are needed to clarify the mechanism of its tissue specificity expression.

Vaspin signaling pathway

  1. Vaspin signaling pathway cascade
    The vaspin signaling pathway has been shown to play a role in different diseases and signaling pathways. Studies have shown that vaspin may attenuate atherosclerosis through the following varieties of mechanisms: (1) Up-regulation of the PI3-K/Akt signaling pathway and inhibition free fatty acid-induced apoptosis of vascular endothelial cells (VEC); (2) Inhibition of p38/hsp27 signaling pathway and reduction of reactive oxygen species (ROS) production, further inhibition of platelet-derived growth factor-BB (PDGF-BB) so as to induce migration of vascular smooth muscle cells; (3) Inhibiting NF-κB signaling pathway after activation of AMPK, and reducing TNF-α-induced adhesion by inhibition of ROS production and activation of NF-κB and PKC expression of molecular ICAM-1, thereby inhibiting the binding of specific receptors on the surface of vascular endothelial cells to ICAM-1; (4) Reducing the level of asymmetric dimethylarginine (AMDA) and increasing nitric oxide synthase and nitric oxide (NO) levels so as to promote vasodilation and improve hypertension and atherosclerosis; (5) Specifically binding to kallikrein enzyme (KLK7), inhibiting KLK7's serine protease hydrolysis activity, and thus alleviating the insulin degradation. Studies by Wada and Tan have found that serum vaspin levels in women with polycystic ovary syndrome are positively correlated with BMI, waist/hip ratio, blood glucose, HOMA-IR, and negatively correlated with insulin sensitivity. Analysis shows that blood glucose plays a decisive role in the change of serum vaspin. The study found that obese mice injected with recombinant vaspin inhibited the expression of leptin, resistin and TNF-α in adipose tissue, and enhanced the gene expression of GLUT-4 and adiponectin. This may be one of the mechanisms by which vaspin improves insulin sensitivity. At present, the influence of vaspin on glucose metabolism and its insulin sensitization is still controversial, and the relationship between them is not clear as well. Researchers find proteases that vaspin action may be helpful in elucidating their effects. Vaspin inhibits apoptosis of human osteoblasts (hOBs); Vaspin stimulates phosphorylation of extracellular signal-regulated kinase (ERK), whereas pretreatment of hOBs with the ERK inhibitor PD98059 blocks vaspin-induced ERK pathway activation; Up-regulation of B lymphoma-2 expression and down-regulation of Bax protein expression inhibit apoptosis of hOBs. In the study of the effect of vaspin on osteogenic differentiation of mouse osteogenic precursor cell (MC3T3-E1) cell line, it was found that vaspin can promote the expression of miR-34C and activate the PI3K-Akt signaling pathway while using specific inhibitors. Blocking the PI3K-Akt signaling pathway attenuates the effect of vaspin on inhibiting osteogenic differentiation while reducing miR-34C expression and reducing miR-34C expression and activating PI3K-Akt signaling, thus miR-34C and PI3K- Akt signal forms a loop that controls the expression of each other. Through this loop, vaspin regulates osteogenic differentiation and inhibits osteoblast differentiation of MC3T3-E1 in a dose-dependent manner. Vaspin also inhibits IL-1β-induced production of catabolic factors and inflammatory mediators in chondrocytes, and inhibits NF-κB phosphorylation and nuclear factor inhibitory protein (IκB-α) degradation to protect cartilage metabolism. Vaspin is closely related to hypertension. Korner found that serum vaspin is negatively correlated with blood pressure and may be associated with vascular endothelial damage. Studies have also shown that serum vaspin levels are negatively correlated with systolic blood pressure in non-coronary patients. In addition to inhibiting vascular cell migration and apoptosis as well as inflammatory responses as mentioned above, recent research suggests that vaspin can have a beneficial effect on high blood pressure in a variety of ways. Kameshima et al isolated the mesenteric artery of male wistar rats, pretreated with vaspin in vitro, and detected markers such as acetylcholinesterase (AChE) activity and eNOS phosphorylation level, and found that vaspin can enhance acetylcholine (ACh)-induced NO, guided diastolic activity, but can not affect the vasoconstriction caused by adrenaline or serotonin. It was first discovered that vaspin can inhibit the activity of acetylcholinesterase and significantly promote acetylcholine-induced eNOS phosphorylation. In addition, it is given to spontaneously hypertensive rats (SHR). Intraperitoneal injection of exogenous vaspin can significantly improve the increase of systolic blood pressure in rats. It is found that vaspin significantly inhibits the hypertrophy of isolated mesenteric artery wall and inhibits the expression of tumor necrosis factor and reactive oxygen species in mesenteric artery, which proves that vaspin can be used for the first time. It can improve the increase of systolic blood pressure by inhibiting peripheral vascular hypertrophy through anti-inflammatory and anti-oxidation mechanisms. Part of the mechanism by which vaspin chronic administration prevents disease progression in spontaneously hypertensive rats is achieved by inhibiting inflammation and remodeling of the vessel wall. Vaspin significantly inhibited the production of reactive oxygen species (ROS) and activation of metalloproteinase-2 (MMP-2) in lung tissue induced by monocrotaline MCT. In addition, IL-1β-induced ROS production and MMP-2 activation in pulmonary artery smooth muscle cells were significantly inhibited. It was demonstrated that vaspin prevents MCT-induced pulmonary hypertension by at least in part inhibiting the ROS/MMP-2/fibrosis pathway.
  2. Pathway regulation
    Like the adiponectin leptin, the level of vaspin is also affected by gender. Tan et al found in vitro that 17-estradiol can increase the expression of vaspin and that in normal women after adjusting for age BMI and waist-to-hip ratio, serum vaspin levels are significantly lower than those of women with polycystic ovary syndrome, but patients with polycystic ovary syndrome are often associated with insulin resistance and impaired glucose tolerance. So, it is not certain whether sex hormones can cause changes in vaspin levels in the body, but Ma et al found the level of vaspin in males is significantly lower than that in females. It is also found that serum vaspin levels can be predicted by gender, and dietary control can also play a role in regulating vaspin. Wang et al. found that through a 16-week, high-fat diet, serum vaspin levels were significantly declined, indicating that vaspin is also regulated by diet and exercise can also affect the expression of vaspin. By exercise, the serum vaspin level of diabetic patients is increased, but for athletes who have been engaged in physical activity for a long time, the serum vaspin level is significantly reduced. This may be related to increased insulin sensitivity in exercise. Drug intervention is also a factor in the regulation of vaspin expression. Both insulin and thiazolidinediones can increase the expression of vaspin in adipose tissue in rats but decrease the effect of serum vaspin on insulin. Thiazolidinediones can increase serum vaspin levels. Metformin also can reduce serum vaspin levels.
  3. Relationship with disease
    Nonalcoholic fatty liver
    Studies have shown that in patients with nonalcoholic fatty liver disease, serum vaspin levels are significantly higher than normal, and vaspin levels are positively correlated with liver fibrosis index and hepatocyte balloon-like variants, while in vitro experiments, inhibition of vaspin production can effectively inhibit the fibrosis process of fatty liver.
    Hypertension/pulmonary hypertension
    Vaspin is closely related to hypertension. Korner A found that serum vaspin is negatively correlated with blood pressure and may be associated with vascular endothelial damage. Studies have also shown that serum vaspin levels are negatively correlated with systolic blood pressure in non-coronary patients. In addition to inhibiting vascular cell migration and apoptosis as well as inflammatory responses as mentioned above, recent studies suggest that vaspin can have beneficial effects on hypertension in a variety of ways.
    Obstructive sleep apnea hypopnea syndrome (osahs)
    Osahs is a clinical syndrome closely related to obesity, diabetes, cardiovascular disease and metabolic disorders. Its pathological basis is chronic intermittent hypoxia. The rat model of chronic intermittent hypoxia has vaspin expression in visceral adipose tissue is significantly increased compared with normal control group, while Akt phosphorylation protein levels decreased in visceral adipose tissue, and visceral adipose tissue and plasma vaspin levels were associated with insulin resistance. In clinical trials, serum vaspin levels were also significantly elevated in osahs patients, and systolic blood pressure and sleep apnea hypopnea index improved after 2 months of nasal continuous positive airway pressure (nCPAP) treatment. Vaspin plays an important role in the occurrence and development of osahs, and further research is needed on its mechanism.

References

  1. Dimova R, Tankova T. The role of vaspin in the development of metabolic and glucose tolerance disorders and atherosclerosis. Biomed Res Int. 2015, 2015:823481.
  2. Zhuang X, Ni Y, Jiang D, et al. Vaspin as a Risk Factor of Insulin Resistance in Obstructive Sleep Apnea-Hypopnea Syndrome in an Animal Model. Clinical Laboratory. 2015, 61(8):883.
  3. Liu P, Li G, Wu J, et al. Vaspin promotes 3T3-L1 preadipocyte differentiation. Experimental Biology & Medicine. 2015, 240(11):1520.
  4. Zhang B, Peng W, Wang K, et al. Vaspin as a Prognostic Marker in Patients with Acute Myocardial Infarction. Heart Lung & Circulation. 2015, 25(3):257-264.
  5. Morisaki T, Takeshima F, Fukuda H, et al. High Serum Vaspin Concentrations in Patients with Ulcerative Colitis. Digestive Diseases & Sciences. 2014, 59(2):315.

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