title: H-RN, a novel antiangiogenic peptide derived from hepatocyte growth factor inhibits inflammation in vitro and in vivo through PI3K/AKT/IKK/NF-κB signal pathway.
abstract: H-RN, a novel antiangiogenic peptide derived from the kringle 1 domain of hepatocyte growth factor (HGF), consists of the sequence RNPRGEEGGPW (molecular weight: 1254.34Da). Emerging evidence indicates that HGF and the kringle domain exhibit anti-inflammatory effects in inflammatory diseases. In the present study, we assessed the anti-inflammatory effect of H-RN in models of experimental ocular inflammation, including endotoxin-induced uveitis (EIU) and experimental autoimmune uveitis (EAU). The results demonstrated that intravitreal treatment of H-RN concentration-dependently suppressed clinical manifestation, inhibited ocular inflammatory cytokine production and improved histopathologic scores. Moreover, H-RN attenuated the LPS-induced mRNA and protein expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in RAW 264.7 cells and inhibited cell chemotactic migration toward LPS. We also demonstrated that H-RN suppressed TNF-α-induced adhesion molecule expression in HUVECs, including ICAM-1, VCAM-1 and E-selectin, which contributed to its suppressive effect on adherence of U937 cells to endothelial cells. We also demonstrated the possible anti-inflammation mechanism of H-RN. Western blot and immunofluorescence staining analyses revealed that H-RN significantly suppressed LPS-induced phosphorylation of nuclear factor (NF)-κB-p65 at Ser276. Based on examination of upstream pathways, we found that H-RN inhibited PI3K-p85 and AKT(Ser473) phosphorylation, which may result in the attenuation of LPS-induced IKK complex activation and IκB degradation. Thus, our studies suggest that the 11-amino-acid peptide H-RN exhibits anti-inflammatory effects in vitro and in vivo and may represent a promising candidate for ocular inflammatory diseases.
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, No. 100, Haining Road, Shanghai, People's Republic of China. Electronic address: drxuxun@126.com.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018920:Coculture Techniques; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology* / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology* / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; C581855:H-RN peptide; D016328:NF-kappa B; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Anti-inflammation; Dexamethasome sodium phosphate (PubChem CID: 16961); Endotoxin-induced uveitis (EIU); Experimental autoimmune uveitis (EAU); Lipopolysaccharide (PubChem CID: 53481793); Nuclear factor (NF)-κB; Peptide