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Kallistatin Inhibits Vascular Inflammation by Antagonizing Tumor Necrosis Factor-α–Induced Nuclear Factor κB Activation
| Content Provider | Scilit |
|---|---|
| Author | Yin, Hang Gao, Lin Shen, Bo Chao, Lee Chao, Julie |
| Copyright Year | 2010 |
| Description | Journal: Hypertension Kallistatin is a plasma protein with anti-inflammatory properties. In this study, we investigated the role and mechanisms of kallistatin in inhibiting endothelial inflammation through its heparin-binding domain. We showed that recombinant wild-type kallistatin dose-dependently competed with tumor necrosis factor (TNF)-α binding to TNF-α receptor in endothelial cells, whereas kallistatin mutant at the heparin-binding domain had no effect. Kallistatin, but not kallistatin mutant at the heparin-binding domain, abrogated TNF-α–induced endothelial cell activation, as evidenced by inhibition of TNF receptor 1–associated death domain protein activation, inhibitor of nuclear factor κB-α degradation, nuclear factor κB translocation, and p38 mitogen-activated protein kinase phosphorylation, as well as cell adhesion molecule and cytokine expression. Moreover, kallistatin, but not kallistatin mutant at the heparin-binding domain, inhibited TNF-α–induced human monocytic THP-1 cell adhesion to endothelial cells and prevented vascular endothelial growth factor–induced endothelial permeability. In mice, kallistatin gene delivery prevented vascular leakage provoked by complement factor C5a, whereas delivery of kallistatin heparin mutant gene had no effect. Similarly, gene transfer of kallistatin, but not the kallistatin heparin mutant, inhibited collagen/adjuvant-induced arthritis in rats. These results indicate that kallistatin’s heparin-binding site plays an essential role in preventing TNF-α–mediated endothelial activation and reducing vascular endothelial growth factor–induced vascular permeability, resulting in attenuation of vascular inflammation in cultured endothelial cells and animal models. This study identifies a protective role of kallistatin in vascular injury, thereby implicating the therapeutic potential of kallistatin for vascular and inflammatory diseases. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922869/pdf https://www.ahajournals.org/doi/pdf/10.1161/HYPERTENSIONAHA.110.152330 |
| Ending Page | 267 |
| Page Count | 8 |
| Starting Page | 260 |
| ISSN | 0194911X |
| e-ISSN | 15244563 |
| DOI | 10.1161/hypertensionaha.110.152330 |
| Journal | Hypertension |
| Issue Number | 2 |
| Volume Number | 56 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2010-08-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Hypertension Nuclear Factor Κb Tumor Necrosis Factor-α Vascular Permeability Vascular Endothelial Growth Factor |
| Content Type | Text |
| Resource Type | Article |
| Subject | Internal Medicine |
