Kallistatin is a new inhibitor of angiogenesis and tumor growth

Miao, Robert Q.; Agata, Jun; Chao, Lee; Chao, Julie

doi:10.1182/blood-2002-01-0185

Cited by 160 publications

(165 citation statements)

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“…30 Kallistatin is a heparin-binding SER-PIN that can inhibit VEGF-mediated angiogenesis by binding to heparin. 31 Similarly, the latent and cleaved form of antithrombin, another heparin binding SERPIN, also has anti-angiogenic activity, 32 and it was recently reported that the latent form of AT down-regulates the expression of the proangiogenic proteoglycan, perlcan, in endothelial cells. 33 Because PCI belongs to the same SERPIN family protein and the vessel number in tumor produced by MDA-PCI cells was significantly decreased as compared to that produced by MDA-Mock cells, we thought that PCI may also exert similar anti-angiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

Asanuma

Yoshikawa

Hayashi

et al. 2007

Intl Journal of Cancer

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Protein C inhibitor (PCI) regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator (uPA), a mediator of tumor cell invasion. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth and metastasis of human breast cancer (MDA-231) cells, and on angiogenesis in vivo. The invasiveness of MDA-231 cells was inhibited by recombinant intact PCI, but not by reactive sitemodified PCI (R354APCI) or by the N-terminal fragment of protease-cleaved PCI (NTPCI). The in vitro invasiveness of MDA-231 cells expressing intact PCI (MDA-PCI) was significantly decreased as compared to MDA-231 cells expressing R354APCI (MDA-R354APCI) or NTPCI (MDA-NTPCI). Further, in vivo growth and metastatic potential of MDA-PCI, MDA-R354APCI and MDA-NTPCI cells in severe combined immunodeficient (SCID) mice were significantly decreased as compared to MDA-Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA-PCI, MDA-R354APCI or MDA-NTPCI cells as compared to that containing MDA-Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti-angiogenic activity of PCI was strong as cleaved antithrombin (AT), and slightly stronger than that of plasminogen activator inhibitor (PAI)-1 and pigment epitheliumderived factor (PEDF). Overall, this study showed that, in addition to a reactive site-dependent mechanism, PCI may also regulate tumor growth and metastasis independently of its protease inhibitory activity by inhibiting angiogenesis. ' 2007 Wiley-Liss, Inc.Key words: protein C inhibitor; serine protease inhibitor; invasion; metastasis; angiogenesis Protein C inhibitor (PCI) was originally identified as a plasma inhibitor of the anticoagulant protease, activated protein C. 1,2 PCI is a member of the serine protease inhibitor (SERPIN) family (SERPINA5); it is also able to inhibit other proteases of the blood coagulation and fibrinolysis system including thrombin, 3 thrombin-thrombomodulin complex, 4 factor Xa, 3 factor XIa, 5 plasma kallikrein 5 and urinary plasminogen activator (uPA). 6 Human plasma PCI is mainly synthesized in the liver, 7 but it is also produced in kidneys and reproductive organs, including testes, seminal vesicles and ovaries. 8,9 Unlike humans, mice and rats produce PCI only in reproductive organs including testes and ovaries 10,11 ; thus, rodents are inappropriate for studying the physiological role of PCI in plasma and other organs. We recently developed a human PCI gene transgenic (TG) mouse in which the tissue distribution of PCI is similar to humans. Using this animal model, we demonstrated that PCI is the physiological inhibitor of APC in plasma, and that it promotes blood coagulation and inflammation in animals with endotoxemia. 12 PCI appears to have also a function in fertilization; Uhrin et al. 13 reported that PCI knock-out male mice have infertility due to abnormal spermatogenesis caused by destruc...

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Section: Discussionmentioning

confidence: 99%

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

Asanuma

Yoshikawa

Hayashi

et al. 2007

Intl Journal of Cancer

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“…Recent studies indicate that kallistatin exerts pleiotropic effects such as vasodilation and inhibition of angiogenesis, tumor growth, inflammation, and oxidative stress, independent of tissue kallikrein (3)(4)(5)(6)(7). We showed that an intravenous bolus injection of human kallistatin caused a rapid and transient reduction of mean arterial blood pressure in anesthetized rats and that kallistatin induced relaxation in isolated aorta rings (3).…”

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confidence: 93%

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Shen

Smith

Hsu

et al. 2009

Journal of Biological Chemistry

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Kallistatin is a plasma protein that exhibits pleiotropic effects in vasodilation, anti-angiogenesis, and anti-inflammation. To isolate a kallistatin-binding protein that mediates the vascular actions of kallistatin, we screened and identified a positive clone from a human heart cDNA expression library by using an alkaline phosphatase-kallistatin fusion protein binding assay. Sequence analysis revealed that kallistatin-binding protein is human Kruppel-like factor 4 (KLF4). KLF4 was localized on the plasma membrane of HEK-293 cells and endothelial cells overexpressing KLF4. KLF4 and kallistatin complex formation was identified in endothelial cells by immunoprecipitation followed by immunoblotting. We showed that kallistatin inhibits tumor necrosis factor-␣-induced NF-B activation, as well as vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression in endothelial cells, whereas knockdown of KLF4 by small interfering RNA oligonucleotide abolished the effect of kallistatin. Kallistatin increased endothelial nitric-oxide synthase (eNOS) expression and nitric oxide levels, and these effects were also blocked by KLF4 small interfering RNA oligonucleotide. Moreover, inhibition of eNOS by RNA interference or by NOS inhibitor abolished the blocking effect of kallistatin on vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression. In summary, we identified KLF4 as a kallistatin-binding protein, which has a novel role in mediating the anti-inflammatory actions of kallistatin via increasing eNOS expression in endothelial cells. This study provides a new target for modulating endothelial function in vascular disease.Kallistatin was discovered as a tissue kallikrein inhibitor from human plasma (1, 2). Recent studies indicate that kallistatin exerts pleiotropic effects such as vasodilation and inhibition of angiogenesis, tumor growth, inflammation, and oxidative stress, independent of tissue kallikrein (3-7). We showed that an intravenous bolus injection of human kallistatin caused a rapid and transient reduction of mean arterial blood pressure in anesthetized rats and that kallistatin induced relaxation in isolated aorta rings (3). Moreover, a high affinity binding site for kallistatin was identified in the aortic membrane using 125 Ilabeled kallistatin (3). Furthermore, kallistatin directly stimulated the proliferation and migration of cultured vascular smooth muscle cells by activating mitogen-activated protein kinases (8). These findings suggest the presence of kallistatin receptors or binding proteins that mediate its effects in the vasculature. However, the identity of the kallistatin receptor/ binding protein has not been determined.Kallistatin is a negative acute-phase protein, which is reduced after acute lipopolysaccharide-induced inflammation and in chronic inflammatory disease (9). Transgenic mice overexpressing kallistatin are more resistant to lipopolysaccharideinduced lethality (10). Kallistatin administration via gene delivery significantly decreased neutroph...

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“…8 Kallistatin is a member of the serine proteinase inhibitor (serpin) superfamily and was shown to have pleiotropic effects, including hypotension, anti-angiogenesis and antiinflammation. [9][10][11] Kallistatin gene delivery reduced ischemic myocardial inflammation and cardiomyocyte apoptosis at 1 day after acute ischemia/reperfusion injury. 12 Recently, we observed that increased oxidative stress after MI was associated with reduced circulating kallistatin levels, suggesting that kallistatin might be involved in the progression of oxidative cardiac damage.…”

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confidence: 99%

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

Gao

Yin

Smith

et al. 2008

Laboratory Investigation

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Oxidative stress causes cardiomyocyte death and subsequent ventricular dysfunction and cardiac remodeling after myocardial infarction (MI), thus contributing to high mortality in chronic heart failure patients. We investigated the effects of kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human kallistatin gene was injected intramyocardially 20 min after ligation of the left coronary artery. At 4 weeks after MI, expression of human kallistatin in rat hearts was identified by reverse transcription-polymerase chain reaction, immunohistochemistry and ELISA. Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased myocardial infarct size and restored left ventricular wall thickness. Kallistatin treatment significantly attenuated cardiomyocyte size and atrial natriuretic peptide expression. Kallistatin also reduced collagen accumulation, collagen fraction volume and expression of collagen types I and III, transforming growth factor-b1 (TGF-b1) and plasminogen activator inhibitor-1 in the myocardium. Inhibition of cardiac hypertrophy and fibrosis by kallistatin was associated with increased cardiac nitric oxide (NO) levels and decreased superoxide formation, NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant kallistatin inhibited intracellular superoxide formation induced by H 2 O 2 , and the antioxidant effect of kallistatin was abolished by No-nitro-L-arginine methyl ester (L-NAME), indicating a NO-mediated event. Kallistatin promoted survival of cardiomyocytes subjected to H 2 O 2 treatment, and inhibited H 2 O 2 -induced Akt and ERK phosphorylation, as well as NF-kB activation. Furthermore, kallistatin abrogated TGF-b-induced collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that kallistatin improves cardiac performance and prevents post-MI-induced cardiac hypertrophy and fibrosis through its antioxidant action. Myocardial infarction (MI) leads to cardiac remodeling with complex structural alterations. After an ischemic insult, left ventricle (LV) enlargement is followed by progressive diastolic stiffness, enhanced wall stress and oxygen consumption, thus resulting in cardiomyocyte hypertrophy, interstitial fibrosis and decreased cardiac output. Increased reactive oxygen species (ROS) levels are recognized to be involved in ischemic heart failure and considered to be a major cause of cardiomyocyte death, ventricular dysfunction and heart failure progress. 1 Under pathological conditions, increased oxidative stress damages DNA and mitochondrial function, activates proapoptotic signaling kinases and leads to myocyte apoptosis or necrosis. 2,3 Elevation of ROS activates a series of hypertrophic signaling kinases and transcription factors to stimulate cardiac hypertrophy. 3,4 Moreover, ROS stimulate fibroblast proliferation and activate the expression of profibrotic factors, including transforming growth...

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Kallistatin is a new inhibitor of angiogenesis and tumor growth

Cited by 160 publications

References 49 publications

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

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