Home Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress
Article Publicly Available

Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress

  • Julie Chao EMAIL logo , Pengfei Li and Lee Chao
Published/Copyright: July 25, 2017
Download Article (PDF)
Biological Chemistry
From the journal Biological Chemistry Volume 398 Issue 12

Abstract

Kallistatin, via its two structural elements – an active site and a heparin-binding domain – displays a double-edged function in angiogenesis, apoptosis and oxidative stress. First, kallistatin has both anti-angiogenic and pro-angiogenic effects. Kallistatin treatment attenuates angiogenesis and tumor growth in cancer-bearing mice. Kallistatin via its heparin-binding site inhibits angiogenesis by blocking vascular endothelial growth factor (VEGF)-induced growth, migration and adhesion of endothelial cells. Conversely, kallistatin via the active site promotes neovascularization by stimulating VEGF levels in endothelial progenitor cells. Second, kallistatin inhibits or induces apoptosis depending on cell types. Kallistatin attenuates organ injury and apoptosis in animal models, and its heparin-binding site is essential for blocking tumor necrosis factor (TNF)-α-induced apoptosis in endothelial cells. However, kallistatin via its active site induces apoptosis in breast cancer cells by up-regulating miR-34a and down-regulating miR-21 and miR-203 synthesis. Third, kallistatin can act as an antioxidant or pro-oxidant. Kallistatin treatment inhibits oxidative stress and tissue damage in animal models and cultured cells. Kallistatin via the heparin-binding domain antagonizes TNF-α-induced oxidative stress, whereas its active site is crucial for stimulating antioxidant enzyme expression. In contrast, kallistatin provokes oxidant formation, leading to blood pressure reduction and bacterial killing. Kallistatin-mediated vasodilation is partly mediated by H2O2, as the effect is abolished by the antioxidant enzyme catalase. Moreover, kallistatin exerts a bactericidal effect by stimulating superoxide production in neutrophils of mice with microbial infection as well as in cultured immune cells. Thus, kallistatin’s dual roles in angiogenesis, apoptosis and oxidative stress contribute to its beneficial effects in various diseases.

Keywords: angiogenesis; apoptosis; cancer; kallistatin; organ injury; oxidative stress

Introduction

Kallistatin was first identified in human plasma as a tissue kallikrein-binding protein (KBP), and a unique serine proteinase inhibitor (serpin) (Chao et al., 1986; Zhou et al., 1992; Chai et al., 1993; Chao and Chao, 1995; Chen et al., 2000a,b). Kallistatin has subsequently been observed to exert a wide spectrum of biological activities independent of its interaction with tissue kallikrein (TK) (Chao et al., 1990; Miao et al., 2002, 2003; Wang et al., 2005; Gao et al., 2008; Shen et al., 2008, 2010a,b; Yin et al., 2010). The structural elements of kallistatin – an active site and a heparin-binding domain (Chen et al., 2000a,b, 2001) – regulate differential signaling pathways and biological functions (Xiong et al., 1992; Chen et al., 1995; Shen et al., 2009; Yin et al., 2010; Zhang et al., 2013; Li et al., 2014, 2015, 2016; Guo et al., 2015). Kallistatin’s active site is essential for: (1) inhibiting TK’s enzymatic activity and bioavailability (Xiong et al., 1992; Chen et al., 2000a,b); (2) stimulating endothelial nitric oxide synthase (eNOS) expression and activation in endothelial cells and endothelial progenitor cells (EPCs) (Shen et al., 2009, 2010a,b; Guo et al., 2015); (3) increasing sirtuin 1 (SIRT1) and suppressor of cytokine signaling 3 (SOCS3) expression in endothelial cells and macrophages (Guo et al., 2015; Li et al., 2015); (4) stimulating miR-34a and inhibiting miR-21 and miR-203 synthesis in breast cancer cells (Li et al., 2016); and (5) interacting with cell surface tyrosine kinase (Guo et al., 2015; Li et al., 2015). Kallistatin via its heparin-binding domain binds to cell surface heparan sulfate proteoglycans, thereby antagonizing the biological effects of: (1) vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability (Miao et al., 2003; Yin et al., 2010); (2) tumor necrosis factor (TNF)-α-induced inflammation, oxidative stress and apoptosis (Shen et al., 2010a,b; Yin et al., 2010; Gao et al., 2014); (3) high mobility group box 1 (HMGB1)-induced inflammation (Li et al., 2014); (4) transforming growth factor (TGF)-β-induced fibrosis and endothelial-mesenchymal transition (EndMT) (Shen et al., 2008; Guo et al., 2015); (5) Wnt-modulated cancer cell proliferation, invasion, and autophagy (Zhang et al., 2013; Li et al., 2016); and (6) epidermal growth factor (EGF)-mediated cancer cell migration and invasion (Chao et al., 2017). Therefore, kallistatin’s pleiotropic activities exert numerous effects in various diseases.

Kallistatin is mainly expressed in the liver, and widely distributed in tissues relevant to cardiovascular function, including the heart, kidney and blood vessels (Chao and Chao, 1995; Chen et al., 1995; Wolf et al., 1999). Circulating kallistatin levels are markedly reduced in hypertension, liver disease, sepsis, cardiac and renal injury, severe pneumonia, obesity and cancer in both patients and animal models (Chao and Chao, 1988; Chao et al., 1990, 1992, 1996a,b, 2016; Hatcher et al., 1997; Stadnicki et al., 2003; Luo et al., 2007; Shen et al., 2008; Lin et al., 2013; Zhu et al., 2013; Cheng et al., 2015). Transgenic mice overexpressing kallistatin have a lower blood pressure compared to control mice, and are also resistant to lipopolysaccharide-induced inflammation and mortality (Chen et al., 1996, 1997a,b). Moreover, kallistatin gene or protein delivery in rodents alleviates the pathological conditions of hypertension, vascular, cardiac and renal injury, tumor growth and metastasis, liver fibrosis, bacterial or virus infection, and septic shock (Chen et al., 1996, 1997a,b; Chao et al., 1997, 2006; Miao et al., 2002; Diao et al., 2007; Lu et al., 2007; Zhu et al., 2007; Gao et al., 2008; Shen et al., 2008; Shiau et al., 2010; Yin et al., 2010; Huang et al., 2014a,b; Li et al., 2014, 2015; Guo et al., 2015; Leu et al., 2015; Lin et al., 2015; Yiu et al., 2016). Importantly, kallistatin’s multi-factorial actions are partly attributed to its double-edged actions in angiogenesis, apoptosis and oxidative stress.

Angiogenesis

Kallistatin’s anti-angiogenic effects

Angiogenesis is an important process in cancer development. Kallistatin administration retards the growth and metastasis of breast, colon, stomach, lung and liver carcinomas by inhibiting tumor-associated angiogenesis in animal models (Miao et al., 2002; Diao et al., 2007; Lu et al., 2007; Zhu et al., 2007; Shiau et al., 2010; Jia et al., 2014). A single intramural injection of the kallistatin gene into pre-established breast cancer xenografts in mice resulted in significant suppression of tumor growth and reduction of micro-vessel density (Miao et al., 2002). Moreover, systemic injection of lentivirus carrying the human kallistatin gene in mice dramatically decreased angiogenesis, inflammation and tumor metastasis into the lung (Shiau et al., 2010). Likewise, kallistatin treatment suppressed tumor growth, angiogenesis and VEGF synthesis in gastric and liver cancer xenografts in mice (Lu et al., 2007; Zhu et al., 2007). VEGF is a key regulator in the development of new blood vessels and tumor growth (O’Byrne et al., 2000; Yeo et al., 2014). Kallistatin via its heparin-binding site antagonized VEGF-induced proliferation, migration and capillary tube formation, as well as vascular permeability of cultured endothelial cells (Miao et al., 2003; Yin et al., 2010). Furthermore, kallistatin prevented elevation of VEGF expression induced by Wnt in cancer cells, and by TNF-α in endothelial cells (Zhang et al., 2013; Huang et al., 2014a,b). Thus, kallistatin through the heparin-binding site inhibits angiogenesis by interfering with VEGF-mediated vascularization inhibiting VEGF expression (Figure 1).

Figure 1: Double-edged role of kallistatin in angiogenesis.
Figure 1:

Double-edged role of kallistatin in angiogenesis.

Kallistatin’s pro-angiogenic effects

EPCs are a continuous source of replenishment for damaged blood vessels by enhancing neovascularization in response to endothelial injury (Umemura and Higashi, 2008; Mikirova et al., 2009). Decreased numbers of circulating EPCs have been observed in patients with hypertension, chronic renal failure, coronary artery disease, diabetes, rheumatoid arthritis and sepsis (Choi et al., 2004; Grisar et al., 2005; Umemura and Higashi, 2008; Cribbs et al., 2012). Reduced EPC numbers may be attributed to defective mobility and proliferation, or accelerated apoptosis and senescence. Therefore, augmented mobilization of endogenous EPCs from bone marrow is an alternative and effective means to promote angiogenesis and vascular repair. In deoxycorticosterone acetate-salt hypertensive rats, kallistatin administration increased circulating EPC number and reduced aortic oxidative stress and endothelial loss, whereas kallistatin deficiency further decreased EPC levels and exacerbated vascular oxidative stress and endothelial rarefaction (Liu et al., 2012; Gao et al., 2014). Thus, kallistatin protects against vascular injury by promoting EPC mobility and function in hypertensive rats. Mechanistically, kallistatin’s active site is key for stimulating the proliferation, migration, adhesion and tube formation of EPCs by activating Akt-eNOS signaling, and increasing VEGF levels (Gao et al., 2014, 2015). Moreover, kallistatin via its active site elevated the expression levels of eNOS and SIRT1 in endothelial cells; however, kallistatin’s effect was blocked by genistein, indicating a tyrosine kinase-mediated event (Gao et al., 2014; Guo et al., 2015). Therefore, kallistatin through its active site promotes angiogenesis and vascular repair by stimulating the mobility and function of EPCs (Figure 1).

Apoptosis

Kallistatin’s anti-apoptotic effects

Oxidative stress induces tissue damage, cellular apoptosis and senescence (Finkel and Holbrook, 2000; Chao et al., 2016). Kallistatin gene transfer attenuated oxidative stress, apoptosis and organ damage in association with increased eNOS levels in rats with myocardial ischemia/reperfusion, myocardial infarction and salt-induced hypertension (Chao et al., 2006; Gao et al., 2008; Shen et al., 2008, 2010a,b). In addition, kallistatin treatment decreased apoptosis and inflammation in mice with polymicrobial sepsis (Li et al., 2014, 2015; Lin et al., 2015). Kallistatin via its heparin-binding site blocked TNF-α-induced oxidative stress and apoptosis via activation of the phosphoinositide 3-kinase (PI3K)-Akt-eNOS signaling pathway in endothelial cells and EPCs (Shen et al., 2010a,b; Yin et al., 2010; Gao et al., 2014). Kallistatin also antagonized TNF-α-mediated suppression of eNOS synthesis and NO formation in EPCs (Guo et al., 2017). Furthermore, kallistatin via its active site stimulated eNOS synthesis by interacting with Kruppel-like factor-(KLF)-4, and increased eNOS activity by activating the PI3K-Akt pathway, leading to elevated NO formation (Shen et al., 2009, 2010a,b; Guo et al., 2015). NO, in turn, is capable of inhibiting NAD(P)H oxidase activity and reactive oxygen species (ROS) formation (Fujii et al., 1997). Thus, kallistatin, through its two structural elements, exerts anti-apoptotic effects by inhibiting oxidative stress and increasing NO production (Figure 2).

Figure 2: Double-edged role of kallistatin in apoptosis.
Figure 2:

Double-edged role of kallistatin in apoptosis.

Kallistatin’s pro-apoptotic effects

MicroRNAs are endogenous non-coding RNA molecules that affect a wide variety of biological processes, including apoptosis, proliferation, organ injury and cancer (Ng et al., 2009; Natarajan et al., 2015). Overexpression of miR-34a induced apoptosis and inhibited the proliferation and migration of breast cancer cells (Li et al., 2013; Yang et al., 2013; Deng et al., 2014). Conversely, miR-21 was significantly increased and associated with poor survival of breast cancer patients (Yan et al., 2008). miR-203 is overexpressed in human breast cancer, while knockdown of miR-203 sensitized cisplatin-mediated apoptotic cell death (Ru et al., 2011). Kallistatin incubation induced apoptosis and autophagy in MDA-MB-231 cancer cells (Li et al., 2016). Kallistatin’s active site is essential for stimulating miR-34a and suppressing miR-21 and miR-203 synthesis in breast cancer cells (Li et al., 2016). Moreover, kallistatin via its heparin-binding site increased peroxisome proliferator-activated receptor γ (PPARγ) synthesis by inhibiting Wnt signaling in cancer cells (Li et al., 2016). In cultured colorectal cancer cells, kallistatin (SERPINA3K) induced apoptosis by activating the PPARγ-Fas-FasL signaling pathway (Yao et al., 2013). Therefore, kallistatin inhibits tumor progression, in part, by inducing cancer cell death through up-regulation of miR-34a and down-regulation of miR-21 and miR-203 synthesis, as well as preventing Wnt-mediated suppression of PPARγ signaling (Figure 2).

Oxidative stress

Kallistatin’s antioxidative effects

ROS stimulate inflammatory pathways and induce cellular apoptosis and senescence (Finkel and Holbrook, 2000; Chao et al., 2016). Reduced kallistatin levels are correlated with increased oxidative organ damage in animal models of hypertension, cardiovascular and renal damage (Shen et al., 2008, 2010a,b; Chao et al., 2016). Kallistatin administration attenuated superoxide formation, inflammation and organ damage associated with increased eNOS and NO levels in animal models of acute and chronic myocardial damage, and salt-induced hypertension (Gao et al., 2008; Shen et al., 2008, 2010a,b). Conversely, depletion of endogenous kallistatin by neutralizing antibody injection augmented cardiovascular and renal damage, increased oxidative stress, inflammation, endothelial cell loss and fibrosis in hypertensive rats (Liu et al., 2012). Kallistatin’s heparin-binding site is necessary for blocking TNF-α-induced NADPH oxidase activity and expression, and its active site is key for stimulating the expression levels of the antioxidant enzymes eNOS, SIRT1 and catalase in endothelial cells and EPCs (Shen et al., 2010a,b; Gao et al., 2014; Guo et al., 2015). Kallistatin, via NO formation, inhibited superoxide production and NAD(P)H oxidase activity induced by TNF-α, TGF-β, H2O2, or angiotensin II in cultured renal epithelial tubular and mesangial cells, cardiomyocytes, myofibroblasts, endothelial cells, and EPCs (Chao et al., 2006; Gao et al., 2008, 2014; Shen et al., 2008, 2009, 2010a,b; Yin et al., 2010; Zhou et al., 2012; Huang et al., 2014a,b; Guo et al., 2015). Likewise, kallistatin (SERPINA3K) exhibited antioxidant activity in cultured pterygium epithelial cells through inhibition of ROS formation (Zhu et al., 2014). Moreover, kallistatin inhibited liver fibrosis via antioxidative stress (Huang et al., 2014a,b). Collectively, kallistatin, via its two functional, elements protects against multi-organ damage through its antioxidative actions (Figure 3).

Figure 3: Double-edged role of kallistatin in oxidative stress.
Figure 3:

Double-edged role of kallistatin in oxidative stress.

Kallistatin’s pro-oxidative effects

Kallistatin induces vasodilation by H2O2 formation

Oxidative stress has both deleterious and beneficial actions. Besides its detrimental effects, ROS also function as a second messenger in intracellular signaling mechanisms that control cell function (Burgoyne et al., 2007). Indeed, H2O2 has been identified as an endothelium-derived hyperpolarizing factor in animals and humans (Matoba et al., 2000; Shimokawa and Morikawa, 2005). H2O2 promotes vasorelaxation by stimulating the dimerization of the redox sensing cGMP-dependent protein kinase (protein kinase G, PKG) isoform PKGIα (Hofmann et al., 2006; Burgoyne et al., 2007). NO, generated by eNOS, diffuses from endothelium to vascular smooth muscle to activate cytosolic guanylate cyclase and trigger cGMP production and PKGIα activation (Hofmann et al., 2006; Burgoyne et al., 2007; Hartzell, 2007). NO has also been shown to be involved in the endothelium-dependent relaxation induced by H2O2 (Zembowicz et al., 1993), and H2O2 up-regulates eNOS transcription and eNOS mRNA half-life (Drummond et al., 2000). Thus, H2O2-induced relaxation in the aorta has both endothelium-dependent and -independent components. Therefore, both H2O2 and NO induce vasodilation through activation of PKGIα.

Kallistatin is a potent vasodilator independent of the tissue kallikrein-kinin system (Chao et al., 1997). An intravenous bolus injection of purified kallistatin caused a rapid and transient reduction of blood pressure in both normotensive and hypertensive rats (Chao et al., 1997, 2016). Kallistatin’s active site is essential for its blood pressure-lowering effect, as wild-type kallistatin and heparin-binding site mutant kallistatin, but not active site mutant kallistatin, induced vasodilation (Chao et al., 2016). Moreover, administration of a NOS inhibitor (Nω-nitro-L-arginine methylester, L-NAME) blocked kallistatin-induced vasodilating activity, indicating an NO-mediated event (Chao et al., 2016). Indeed, kallistatin via its active site activates Akt-eNOS signaling, and thus NO formation, in endothelial cells and EPCs (Shen et al., 2010a,b; Gao et al., 2014; Guo et al., 2015). In addition, kallistatin-induced vasodilation is mediated by H2O2, as kallistatin’s blood pressure-lowering effect was abolished by the antioxidant enzyme catalase (Figure 4A). Furthermore, kallistatin time-dependently induced H2O2 formation in cultured endothelial and vascular smooth muscle cells (Figure 4B, C). Likewise, in isolated aortic segments, kallistatin increased H2O2 formation and PKGIα dimerization under non-reducing conditions (Figure 4D, E). Therefore, kallistatin via its active site induces vasodilation by generation of H2O2 and NO, and thus PKGIα activation in blood vessels (Figure 3). Kallistatin-induced oxidant formation is partly mediated by protein kinase C (PKC) activation, as time-dependent stimulation of H2O2 production by kallistatin in endothelial cells and vascular smooth muscle cells is blocked by chelerythrine, a PKC inhibitor (unpublished results). The signaling mechanisms of kallistatin’s pro-oxidative effect remain to be further elucidated.

Figure 4: Kallistatin induces vasodilation by H2O2 formation.Kallistatin’s vasodilatory effect is partly mediated by H2O2 formation, as the effect is blocked by catalase (A). Kallistatin stimulates endogenous H2O2 formation in endothelial cells (B), and vascular smooth muscle cells (C). In isolated aorta, kallistatin induces H2O2 formation (D) and PKGIα dimerization (E). *p<0.05 compared to the control group.
Figure 4:

Kallistatin induces vasodilation by H2O2 formation.

Kallistatin’s vasodilatory effect is partly mediated by H2O2 formation, as the effect is blocked by catalase (A). Kallistatin stimulates endogenous H2O2 formation in endothelial cells (B), and vascular smooth muscle cells (C). In isolated aorta, kallistatin induces H2O2 formation (D) and PKGIα dimerization (E). *p<0.05 compared to the control group.

Kallistatin induces bacterial killing by stimulating ROS formation

Oxidative stress has been shown to have beneficial effects with bacterial killing activity in inflammatory disorders (Babior, 2000; Splettstoesser and Schuff-Werner, 2002). Kallistatin treatment exhibited a marked bacterial killing effect and significantly promoted the survival of mice with streptococcal infection and polymicrobial sepsis (Lu et al., 2013; Li et al., 2014). The bactericidal activity of kallistatin is most likely attributed to elevated ROS formation in peritoneal neutrophils (Lu et al., 2013). Moreover, kallistatin significantly enhanced clearance of E. coli in conjunction with increased NADPH oxidase expression and activity in neutrophil-like HL-60 cells (Figure 5A–C). Thus, it is likely that kallistatin exerts bactericidal activity by stimulating ROS formation in the immune cells of mice with bacterial infection (Figure 3).

Figure 5: Kallistatin treatment reduces bacterial number, and increases NADPH oxidase expression and activity in neutrophil-like HL-60 cells.*p<0.05 compared to the control group.
Figure 5:

Kallistatin treatment reduces bacterial number, and increases NADPH oxidase expression and activity in neutrophil-like HL-60 cells.

*p<0.05 compared to the control group.

Conclusions

Kallistatin is an endogenous protein with dual roles in angiogenesis, apoptosis and oxidative stress. Kallistatin inhibits angiogenesis and tumor growth in animal models. Kallistatin, via its heparin-binding domain, inhibits angiogenesis by blocking VEGF-induced effects and TNF-α-induced VEGF synthesis, while its active site is crucial for stimulating neovascularization by increasing eNOS and VEGF levels. Moreover, kallistatin attenuates apoptosis and tissue injury in animal models with hypertension and cardiac dysfunction. Kallistatin, via its heparin-binding domain, antagonizes TNF-α-induced apoptosis in endothelial and renal cells, while its active site is crucial for inducing cancer cell apoptosis by stimulating miR-34a and inhibiting miR-21 and miR-203 synthesis. Furthermore, kallistatin attenuates oxidative stress and multi-organ injury in animal models. Kallistatin, via its heparin-binding site, antagonizes cytokine-induced superoxide formation, and its active site is responsible for the stimulation of antioxidant gene expression. In contrast, kallistatin stimulates vascular ROS formation, leading to vasodilation as well as marked bacterial killing activity in immune cells of septic mice. Kallistatin, with its double-edged actions in angiogenesis, apoptosis and oxidative stress, protects against the pathogenesis of hypertension, organ injury, septic syndrome and tumor progression. It has yet to be determined which biological function of kallistatin plays the dominant role in the pathogenesis of diseases. Although the beneficial properties of kallistatin therapy under pathological conditions have been demonstrated in various animal models, future studies are needed to confirm kallistatin’s salutary effects in humans. Collectively, these findings implicate kallistatin as an important player in keeping the balance of biological functions in the normal physiological setting.

Acknowledgements

Our work was supported by the National Institutes of Health grants HL118516 and HL44083.

  1. Conflict of interest statement: The authors declare that they have no conflict of interest.

References

Babior, B.M. (2000). Phagocytes and oxidative stress. Am. J. Med. 109, 33–44.10.1016/S0002-9343(00)00481-2Search in Google Scholar

Burgoyne, J.R., Madhani, M., Cuello, F., Charles, R.L., Brennan, J.P., Schroder, E., Browning, D.D., and Eaton, P. (2007). Cysteine redox sensor in PKGIa enables oxidant-induced activation. Science 317, 1393–1397.10.1126/science.1144318Search in Google Scholar

Chai, K.X., Chen, L.M., Chao, J., and Chao, L. (1993). Kallistatin: a novel human serine proteinase inhibitor. Molecular cloning, tissue distribution, and expression in Escherichia coli. J. Biol. Chem. 268, 24498–24505.10.1016/S0021-9258(20)80553-5Search in Google Scholar

Chao, J. and Chao, L. (1988). A major difference of kallikrein-binding protein in spontaneously hypertensive versus normotensive rats. J. Hypertens. 6, 551–557.10.1097/00004872-198807000-00006Search in Google Scholar

Chao, J. and Chao, L. (1995). Biochemistry, regulation and potential function of kallistatin. Biol. Chem. Hoppe-Seyler 376, 705–713.Search in Google Scholar

Chao, J., Tillman, D.M., Wang, M.Y., Margolius, H.S., and Chao, L. (1986). Identification of a new tissue-kallikrein-binding protein. Biochem J. 239, 325–331.10.1042/bj2390325Search in Google Scholar

Chao, J., Chai, K.X., Chen, L.M., Xiong, W., Chao, S., Woodley-Miller, C., Wang, L.X., Lu, H.S., and Chao, L. (1990). Tissue kallikrein-binding protein is a serpin. I. Purification, characterization, and distribution in normotensive and spontaneously hypertensive rats. J. Biol. Chem. 265, 16394–16401.10.1016/S0021-9258(17)46236-3Search in Google Scholar

Chao, J., Chen, L.M., Chai, K.X., and Chao, L. (1992). Expression of kallikrein-binding protein and alpha 1-antitrypsin genes in response to sex hormones, growth, inflammation and hypertension. Agents Actions Suppl. 38(Pt. 1), 174–181.Search in Google Scholar

Chao, J., Schmaier, A., Chen, L.M., Yang, Z., and Chao, L. (1996a). Kallistatin, a novel human tissue kallikrein inhibitor: levels in body fluids, blood cells, and tissues in health and disease. J. Lab. Clin. Med. 127, 612–620.10.1016/S0022-2143(96)90152-3Search in Google Scholar

Chao, C., Madeddu, P., Wang, C., Liang, Y., Chao, L., and Chao, J. (1996b). Differential regulation of kallikrein, kininogen, and kallikrein-binding protein in arterial hypertensive rats. Am. J. Physiol. 271, F78–F86.10.1152/ajprenal.1996.271.1.F78Search in Google Scholar PubMed

Chao, J., Stallone, J.N., Liang, Y.M., Chen, L.M., Wang, D.Z., and Chao, L. (1997). Kallistatin is a potent new vasodilator. J. Clin. Invest. 100, 11–17.10.1172/JCI119502Search in Google Scholar PubMed PubMed Central

Chao, J., Yin, H., Yao, Y.Y., Shen, B., Smith, R.S., Jr., and Chao, L. (2006). Novel role of kallistatin in protection against myocardial ischemia-reperfusion injury by preventing apoptosis and inflammation. Hum. Gene. Ther. 17, 1201–1213.10.1089/hum.2006.17.1201Search in Google Scholar PubMed

Chao, J., Bledsoe, G., and Chao, L. (2016). Protective role of kallistatin in vascular and organ injury. Hypertension 68, 533–541.10.1161/HYPERTENSIONAHA.116.07861Search in Google Scholar

Chao, J., Li, P., and Chao, L. (2017). Kallistatin suppresses cancer development by multi-factorial actions. Crit. Rev. Oncol. Hematol. 113, 71–78.10.1016/j.critrevonc.2017.03.011Search in Google Scholar

Chen, L.M., Song, Q., Chao, L., and Chao, J. (1995). Cellular localization of tissue kallikrein and kallistatin mRNAs in human kidney. Kidney Int. 48, 690–697.10.1038/ki.1995.339Search in Google Scholar

Chen, L.M., Ma, J., Liang, Y.M., Chao, L., and Chao, J. (1996). Tissue kallikrein-binding protein reduces blood pressure in transgenic mice. J. Biol. Chem. 271, 27590–27594.10.1074/jbc.271.44.27590Search in Google Scholar

Chen, L.M., Chao, L., and Chao, J. (1997a). Adenovirus- mediated delivery of human kallistatin gene reduces blood pressure of spontaneously hypertensive rats. Hum. Gene. Ther. 8, 341–347.10.1089/hum.1997.8.3-341Search in Google Scholar

Chen, L.M., Chao, L., and Chao, J. (1997b). Beneficial effects of kallikrein-binding protein in transgenic mice during endotoxic shock. Life Sci. 60, 1431–1435.10.1016/S0024-3205(97)00094-5Search in Google Scholar

Chen, V.C., Chao, L., and Chao, J. (2000a). Roles of the P1, P2, and P3 residues in determining inhibitory specificity of kallistatin toward human tissue kallikrein. J. Biol. Chem. 275, 38457–38466.10.1074/jbc.M005605200Search in Google Scholar

Chen, V.C., Chao, L., and Chao, J. (2000b). Reactive-site specificity of human kallistatin toward tissue kallikrein probed by site-directed mutagenesis. Biochim. Biophys. Acta 1479, 237–246.10.1016/S0167-4838(00)00044-3Search in Google Scholar

Chen, V.C., Chao, L., Pimenta, D.C., Bledsoe, G., Juliano, L., and Chao, J. (2001). Identification of a major heparin-binding site in kallistatin. J. Biol. Chem. 276, 1276–1284.10.1074/jbc.M005791200Search in Google Scholar PubMed

Cheng, Z., Lv, Y., Pang, S., Bai, R., Wang, M., Lin, S., Xu, T., Spalding, D., Habib, N., and Xu, R. (2015). Kallistatin, a new and reliable biomarker for the diagnosis of liver cirrhosis. Acta Pharm. Sin. B 5, 194–200.10.1016/j.apsb.2015.02.003Search in Google Scholar PubMed PubMed Central

Choi, J.H., Kim, K.L., Huh, W., Kim, B., Byun, J., Suh, W., Sung, J., Jeon, E.S., Oh, H.Y., and Kim, D.K. (2004). Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb. Vasc. Biol. 24, 1246–1252.10.1161/01.ATV.0000133488.56221.4aSearch in Google Scholar PubMed

Cribbs, S.K., Sutcliffe, D.J., Taylor, W.R., Rojas, M., Easley, K.A., Tang, L., Brigham, K.L., and Martin, G.S. (2012). Circulating endothelial progenitor cells inversely associate with organ dysfunction in sepsis. Intensive Care Med. 38, 429–436.10.1007/s00134-012-2480-9Search in Google Scholar PubMed PubMed Central

Deng, X., Cao, M., Zhang, J., Hu, K., Yin, Z., Zhou, Z., Xiao, X., Yang, Y., Sheng, W., Wu, Y., et al. (2014). Hyaluronic acid-chitosan nanoparticles for co-delivery of MiR-34a and doxorubicin in therapy against triple negative breast cancer. Biomaterials 35, 4333–4344.10.1016/j.biomaterials.2014.02.006Search in Google Scholar PubMed

Diao, Y., Ma, J., Xiao, W.D., Luo, J., Li, X.Y., Chu, K.W., Fung, P., Habib, N., Farzaneh, F., and Xu, R.A. (2007). Inhibition of angiogenesis and HCT-116 xenograft tumor growth in mice by kallistatin. World J. Gastroenterol. 13, 4615–4619.10.3748/wjg.v13.i34.4615Search in Google Scholar PubMed PubMed Central

Drummond, G.R., Cai, H., Davis, M.E., Ramasamy, S., and Harrison, D.G. (2000). Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ. Res. 86, 347–354.10.1161/01.RES.86.3.347Search in Google Scholar

Finkel, T. and Holbrook, N.J. (2000). Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247.10.1038/35041687Search in Google Scholar PubMed

Fujii, H., Ichimori, K., Hoshiai, K., and Nakazawa, H. (1997). Nitric oxide inactivates NADPH oxidase in pig neutrophils by inhibiting its assembling process. J. Biol. Chem. 272, 32773–32778.10.1074/jbc.272.52.32773Search in Google Scholar PubMed

Gao, L, Yin, H., Smith, S.R., Jr., Chao, L., and Chao, J. (2008). Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction. Lab. Invest. 88, 1157–1166.10.1038/labinvest.2008.85Search in Google Scholar PubMed

Gao, L., Li, P., Zhang, J., Hagiwara, M., Shen, B., Bledsoe, G., Chang, E., Chao, L., and Chao, J. (2014). Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J. Am. Heart Assoc. 3, e001194.10.1161/JAHA.114.001194Search in Google Scholar PubMed PubMed Central

Grisar, J., Aletaha, D., Steiner, C.W., Kapral, T., Steiner, S., Seidinger, D., Weigel, G., Schwarzinger, I., Wolozcszuk, W., Steiner, G., et al. (2005). Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis. Circulation 111, 204–211.10.1161/01.CIR.0000151875.21836.AESearch in Google Scholar PubMed

Guo, Y., Li, P., Bledsoe, G., Yang, Z.R., Chao, L., and Chao, J. (2015). Kallistatin inhibits TGF-β-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp. Cell Res. 337, 103–110.10.1016/j.yexcr.2015.06.021Search in Google Scholar PubMed PubMed Central

Guo, Y., Li, P., Gao, L., Zhang, J., Yang, Z., Bledsoe, G., Chang, E., Chao, L., and Chao, J. (2017). Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway. Aging Cell 16, 837–846.10.1111/acel.12615Search in Google Scholar PubMed PubMed Central

Hartzell, H.C. (2007). Cell biology. The stress of relaxation. Science 317, 1331–1332.10.1126/science.1148142Search in Google Scholar PubMed

Hatcher, H.C., Ma, J.X., Chao, J., Chao, L., and Ottlecz, A. (1997). Kallikrein-binding protein levels are reduced in the retinas of streptozotocin-induced diabetic rats. Invest. Ophthalmol. Vis. Sci. 38, 658–664.Search in Google Scholar

Hofmann, F., Feil, R., Kleppisch, T., and Schlossmann, J. (2006). Function of cGMP-dependent protein kinases as revealed by gene deletion. Physiol. Rev. 86, 1–23.10.1152/physrev.00015.2005Search in Google Scholar PubMed

Huang, K.F., Huang, X.P., Xiao, G.Q., Yang, H.Y., Lin, J.S., and Diao, Y. (2014a). Kallistatin, a novel anti-angiogenesis agent, inhibits angiogenesis via inhibition of the NF-κB signaling pathway. Biomed. Pharmacother. 68, 455–461.10.1016/j.biopha.2014.03.005Search in Google Scholar PubMed

Huang, X., Wang, X., Lv, Y., Xu, L., Lin, J., and Diao, Y. (2014b). Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress. PLoS One 9, e88498.10.1371/journal.pone.0088498Search in Google Scholar PubMed PubMed Central

Jia, D., Zheng, C., Feng, J., Zou, J., and Diao, Y. (2014). Plasmid mediated kallistain gene expression via intramuscular electroporation delivery in vivo for treatment of NCI-H446 subcutaneous xenograft tumor. Pak. J. Pharm. Sci. 27, 633–636.Search in Google Scholar

Leu, C.H., Yang, M.L., Chung, N.H., Huang, Y.J., Su, Y.C., Chen, Y.C., Lin, C.C., Shieh, G.S., Chang, M.Y., Wang, S.W., et al. (2015). Kallistatin ameliorates influenza virus pathogenesis by inhibition of kallikrein-related peptidase 1-mediated cleavage of viral hemagglutinin. Antimicrob. Agents Chemother. 59, 5619–5630.10.1128/AAC.00065-15Search in Google Scholar PubMed PubMed Central

Li, L., Yuan, L., Luo, J., Gao, J., Guo, J., and Xie, X. (2013). MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin. Exp. Med. 13, 109–117.10.1007/s10238-012-0186-5Search in Google Scholar PubMed

Li, P., Bledsoe, G., Yang, Z.R., Fan, H., Chao, L., and Chao, J. (2014). Human kallistatin administration reduces organ injury and improves survival in a mouse model of polymicrobial sepsis. Immunology 142, 216–226.10.1111/imm.12242Search in Google Scholar PubMed PubMed Central

Li, P., Guo, Y., Bledsoe, G., Yang, Z.R., Fan, H., Chao, L., and Chao, J. (2015). Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis. Crit. Care 19, 200.10.1186/s13054-015-0919-4Search in Google Scholar PubMed PubMed Central

Li, P., Guo, Y., Bledsoe, G., Yang, Z., Chao, L., and Chao, J. (2016). Kallistatin induces breast cancer cell apoptosis and autophagy by modulating Wnt signaling and microRNA synthesis. Exp. Cell Res. 340, 305–314.10.1016/j.yexcr.2016.01.004Search in Google Scholar PubMed PubMed Central

Lin, W.C., Lu, S.L., Lin, C.F., Chen, C.W., Chao, L., Chao, J., and Lin, Y.S. (2013). Plasma kallistatin levels in patients with severe community-acquired pneumonia. Crit. Care 17, R27.10.1186/cc12507Search in Google Scholar PubMed PubMed Central

Lin, W.C., Chen, C.W., Huang, Y.W., Chao, L., Chao, J., Lin, Y.S., and Lin, C.F. (2015). Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci. Rep. 5, 12463.10.1038/srep12463Search in Google Scholar PubMed PubMed Central

Liu, Y., Bledsoe, G., Hagiwara, M., Shen, B., Chao, L., and Chao, J. (2012). Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. Am. J. Physiol. Renal. Physiol. 303, F1230–F1238.10.1152/ajprenal.00257.2012Search in Google Scholar PubMed PubMed Central

Lu, L., Yang, Z., Zhu, B., Fang, S., Yang, X., Cai, W., Li, C., Ma, J.X., and Gao, G. (2007). Kallikrein-binding protein suppresses growth of hepatocellular carcinoma by anti-angiogenic activity. Cancer Lett. 257, 97–106.10.1016/j.canlet.2007.07.008Search in Google Scholar PubMed

Lu, S.L., Tsai, C.Y., Luo, Y.H., Kuo, C.F., Lin, W.C., Chang, Y.T., Wu, J.J., Chuang, W.J., Liu, C.C., Chao, L., et al. (2013). Kallistatin modulates immune cells and confers anti-inflammatory response to protect mice from group A streptococcal infection. Antimicrob. Agents Chemother. 57, 5366–5372.10.1128/AAC.00322-13Search in Google Scholar PubMed PubMed Central

Luo, Q., Siconolfi-Baez, L., Annamaneni, P., Bielawski, M.T., Novikoff, P.M., and Angeletti, R.H. (2007). Altered protein expression at early-stage rat hepatic neoplasia. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1272–G1282.10.1152/ajpgi.00474.2006Search in Google Scholar PubMed

Matoba, T., Shimokawa, H., Nakashima, M., Hirakawa, Y., Mukai, Y., Hirano, K., Kanaide H., and Takeshita, A. (2000). Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J. Clin. Invest. 106, 1521–1530.10.1172/JCI10506Search in Google Scholar PubMed PubMed Central

Miao, R.Q., Agata, J., Chao, L., and Chao, J. (2002). Kallistatin is a new inhibitor of angiogenesis and tumor growth. Blood 100, 3245–3252.10.1182/blood-2002-01-0185Search in Google Scholar PubMed

Miao, R.Q., Chen, V., Chao, L., and Chao, J. (2003). Structural elements of kallistatin required for inhibition of angiogenesis. Am. J. Physiol. Cell Physiol. 284, C1604–C1613.10.1152/ajpcell.00524.2002Search in Google Scholar PubMed

Mikirova, N.A., Jackson, J.A., Hunninghake, R., Kenyon, J., Chan, K.W., Swindlehurst, C.A., Minev, B., Patel, A.N., Murphy, M.P., Smith, L., et al. (2009). Circulating endothelial progenitor cells: a new approach to anti-aging medicine? J. Transl. Med. 7, 106.10.1186/1479-5876-7-106Search in Google Scholar

Natarajan, S.K., Pachunka, J.M., and Mott, J.L. (2015). Role of microRNAs in alcohol-induced multi-organ injury. Biomolecules 5, 3309–3338.10.3390/biom5043309Search in Google Scholar

Ng, E.K., Wong, C.L., Ma, E.S., and Kwong, A. (2009). MicroRNAs as new players for diagnosis, prognosis, and therapeutic targets in breast cancer. J. Oncol. 2009, 305420.10.1155/2009/305420Search in Google Scholar

O’Byrne, K.J., Dalgleish, A.G., Browning, M.J., Steward, W.P., and Harris, A.L. (2000). The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. Eur. J. Cancer 36, 151–169.10.1016/S0959-8049(99)00241-5Search in Google Scholar

Ru, P., Steele, R., Hsueh, E.C., and Ray, R.B. (2011). Anti-miR-203 upregulates SOCS3 expression in breast cancer cells and enhances cisplatin chemosensitivity. Genes Cancer 2, 720–727.10.1177/1947601911425832Search in Google Scholar PubMed PubMed Central

Shen, B., Hagiwara, M., Yao, Y.Y., Chao, L., and Chao, J. (2008). Salutary effect of kallistatin in salt-induced renal injury, inflammation, and fibrosis via antioxidative stress. Hypertension 51, 1358–1365.10.1161/HYPERTENSIONAHA.107.108514Search in Google Scholar PubMed

Shen, B., Smith, R.S., Jr., Hsu, Y.T., Chao, L., and Chao, J. (2009). Kruppel-like factor 4 is a novel mediator of kallistatin in inhibiting endothelial inflammation via increased endothelial nitric-oxide synthase expression. J. Biol. Chem. 284, 35471–35478.10.1074/jbc.M109.046813Search in Google Scholar PubMed PubMed Central

Shen, B., Chao, L., and Chao, J. (2010a). Pivotal role of JNK-dependent FOXO1 activation in downregulation of kallistatin expression by oxidative stress. Am. J. Physiol. Heart Circ. Physiol. 298, H1048–H1054.10.1152/ajpheart.00826.2009Search in Google Scholar PubMed PubMed Central

Shen, B., Gao, L., Hsu, Y.T., Bledsoe, G., Hagiwara, M., Chao, L., and Chao, J. (2010b). Kallistatin attenuates endothelial apoptosis through inhibition of oxidative stress and activation of Akt-eNOS signaling. Am. J. Physiol. Heart Circ. Physiol. 299, H1419–H1427.10.1152/ajpheart.00591.2010Search in Google Scholar PubMed PubMed Central

Shiau, A.L., Teo, M.L., Chen, S.Y., Wang, C.R., Hsieh, J.L., Chang, M.Y., Chang, C.J., Chao, J., Chao, L., Wu, C.L., et al. (2010). Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin. BMC Cancer 10, 245.10.1186/1471-2407-10-245Search in Google Scholar PubMed PubMed Central

Shimokawa, H. and Morikawa, K. (2005). Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J. Mol. Cell Cardiol. 39, 725–732.10.1016/j.yjmcc.2005.07.007Search in Google Scholar PubMed

Splettstoesser, W.D. and Schuff-Werner, P. (2002). Oxidative stress in phagocytes – the enemy within. Microsc. Res. Tech. 57, 441–455.10.1002/jemt.10098Search in Google Scholar PubMed

Stadnicki, A., Mazurek, U., Gonciarz, M., Plewka, D., Nowaczyk, G., Orchel, J., Pastucha, E., Plewka, A., Wilczok, T., and Colman, R.W. (2003). Immunolocalization and expression of kallistatin and tissue kallikrein in human inflammatory bowel disease. Dig. Dis. Sci. 48, 615–623.10.1023/A:1022569623350Search in Google Scholar

Umemura, T. and Higashi, Y. (2008). Endothelial progenitor cells: therapeutic target for cardiovascular diseases. J. Pharmacol. Sci. 108, 1–6.10.1254/jphs.08R01CPSearch in Google Scholar

Wang, C.R., Chen, S.Y., Wu, C.L., Liu, M.F., Jin, Y.T., Chao, L., and Chao, J. (2005). Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation. Arthritis Rheum. 52, 1319–1324.10.1002/art.20991Search in Google Scholar PubMed

Wolf, W.C., Harley, R.A., Sluce, D., Chao, L., and Chao, J. (1999). Localization and expression of tissue kallikrein and kallistatin in human blood vessels. J. Histochem. Cytochem. 47, 221–228.10.1177/002215549904700210Search in Google Scholar PubMed

Xiong, W., Tang, C.Q., Zhou, G.X., Chao, L., and Chao, J. (1992). In vivo catabolism of human kallikrein-binding protein and its complex with tissue kallikrein. J. Lab. Clin. Med. 119, 514–521.Search in Google Scholar

Yan, L.X., Huang, X.F., Shao, Q., Huang, M.Y., Deng, L., Wu, Q.L., Zeng, Y.X., and Shao, J.Y. (2008). MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 14, 2348–2360.10.1261/rna.1034808Search in Google Scholar PubMed PubMed Central

Yang, S., Li, Y., Gao, J., Zhang, T., Li, S., Luo, A., Chen, H., Ding, F., Wang, X., and Liu, Z. (2013). MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene 32, 4294–4303.10.1038/onc.2012.432Search in Google Scholar PubMed

Yao, Y., Li, L., Huang, X., Gu, X., Xu, Z., Zhang, Y., Huang, L., Li, S., Dai, Z., Li, C., et al. (2013). SERPINA3K induces apoptosis in human colorectal cancer cells via activating the Fas/FasL/caspase-8 signaling pathway. FEBS J. 280, 3244–3255.10.1111/febs.12303Search in Google Scholar PubMed

Yeo, E.J., Cassetta, L., Qian, B.Z., Lewkowich, I., Li, J.F., Stefater, J.A., 3rd, Smith, A.N., Wiechmann, L.S., Wang, Y., Pollard, J.W., et al. (2014). Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 74, 2962–2973.10.1158/0008-5472.CAN-13-2421Search in Google Scholar PubMed PubMed Central

Yin, H., Gao, L., Shen, B., Chao, L., and Chao, J. (2010). Kallistatin inhibits vascular inflammation by antagonizing tumor necrosis factor-α-induced nuclear factor κB activation. Hypertension 56, 260–267.10.1161/HYPERTENSIONAHA.110.152330Search in Google Scholar

Yiu, W.H., Wong, D.W., Wu, H.J., Li, R.X., Yam, I., Chan, L.Y., Leung, J.C., Lan, H.Y., Lai, K.N., and Tang, S.C. (2016). Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress. Kidney Int. 89, 386–398.10.1038/ki.2015.331Search in Google Scholar

Zembowicz, A., Hatchett, R.J., Jakubowski, A.M., and Gryglewski, R.J. (1993). Involvement of nitric oxide in the endothelium-dependent relaxation induced by hydrogen peroxide in the rabbit aorta. Br. J. Pharmacol. 110, 151–158.10.1111/j.1476-5381.1993.tb13785.xSearch in Google Scholar

Zhang, J., Yang, Z., Li, P., Bledsoe, G., Chao, L., and Chao, J. (2013). Kallistatin antagonizes Wnt/beta-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6. Mol. Cell Biochem. 379, 295–301.10.1007/s11010-013-1654-2Search in Google Scholar

Zhou, G.X., Chao, L., and Chao, J. (1992). Kallistatin: a novel human tissue kallikrein inhibitor. Purification, characterization, and reactive center sequence. J. Biol. Chem. 267, 25873–25880.10.1016/S0021-9258(18)35690-4Search in Google Scholar

Zhou, T., Zong, R., Zhang, Z., Zhu, C., Pan, F., Xiao, X., Liu, Z., He, H., Ma, J.X., and Zhou, Y. (2012). SERPINA3K protects against oxidative stress via modulating ROS generation/degradation and KEAP1-NRF2 pathway in the corneal epithelium. Invest. Ophthalmol. Vis. Sci. 53, 5033–5043.10.1167/iovs.12-9729Search in Google Scholar PubMed

Zhu, B., Lu, L., Cai, W., Yang, X., Li, C., Yang, Z., Zhan, W., Ma, J.X., and Gao, G. (2007). Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis. Mol. Cancer Ther. 6, 3297–3306.10.1158/1535-7163.MCT-06-0798Search in Google Scholar PubMed

Zhu, H., Chao, J., Kotak, I., Guo, D., Parikh, S.J., Bhagatwala, J., Dong, Y., Patel, S.Y., Houk, C., and Chao, L. (2013). Plasma kallistatin is associated with adiposity and cardiometabolic risk in apparently healthy African American adolescents. Metabolism 62, 642–646.10.1016/j.metabol.2012.10.012Search in Google Scholar PubMed PubMed Central

Zhu, C., Pan, F., Ge, L., Zhou, J., Chen, L., Zhou, T., Zong, R., Xiao, X., Dong, N., Yang, M., et al. (2014). SERPINA3K plays antioxidant roles in cultured pterygial epithelial cells through regulating ROS system. PLoS One 9, e108859.10.1371/journal.pone.0108859Search in Google Scholar PubMed PubMed Central

Received: 2017-6-14
Accepted: 2017-7-18
Published Online: 2017-7-25
Published in Print: 2017-11-27

©2017 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology
  4. Cystine knot growth factors and their functionally versatile proregions
  5. Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress
  6. Minireview
  7. The sphingomyelin synthase family: proteins, diseases, and inhibitors
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Comparison of cytochrome P450 expression in four different human osteoblast models
  11. Cell Biology and Signaling
  12. The molecular mechanisms involved in lectin-induced human platelet aggregation
  13. HDAC1 triggers the proliferation and migration of breast cancer cells via upregulation of interleukin-8
  14. Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice
https://doi.org/10.1515/hsz-2017-0180
Keywords for this article
angiogenesis; apoptosis; cancer; kallistatin; organ injury; oxidative stress

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology
  4. Cystine knot growth factors and their functionally versatile proregions
  5. Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress
  6. Minireview
  7. The sphingomyelin synthase family: proteins, diseases, and inhibitors
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Comparison of cytochrome P450 expression in four different human osteoblast models
  11. Cell Biology and Signaling
  12. The molecular mechanisms involved in lectin-induced human platelet aggregation
  13. HDAC1 triggers the proliferation and migration of breast cancer cells via upregulation of interleukin-8
  14. Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 23.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2017-0180/html?lang=en
Scroll to top button