Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver.
Donor organ damage caused by cold preservation is a major problem affecting liver transplantation. Cold preservation most easily damages liver sinusoidal endothelial cells (LSECs), and information about the molecules modulating LSECs function can provide the basis for new therapeutic strategies. Adrenomedullin (AM) is a peptide known to possess anti-apoptotic and anti-inflammatory properties. AM is abundant in vascular endothelial cells, but levels are comparatively low in liver, and little is known about its function there. In this study, we demonstrated both AM and its receptors are expressed in LSECs. AM treatment reduced LSECs loss and apoptosis under cold treatment. AM also downregulated cold-induced expression of TNFalpha, IL1beta, IL6, ICAM1 and VCAM1. AM reduced apoptosis and expression of ICAM1 and VCAM1 in an in vivo liver model subjected to cold storage. Conversely, apoptosis was exacerbated in livers from AM and RAMP2 (AM receptor activity-modifying protein) knockout mice. These results suggest that AM expressed in LSECs exerts a protective effect against cold-organ damage through modulation of apoptosis and inflammation.
Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Japan.
Nobuyoshi
N
Iinuma
Takayuki
T
Sakurai
Akiko
A
Kamiyoshi
Yuka
Y
Ichikawa-Shindo
Takuma
T
Arai
Takahiro
T
Yoshizawa
Teruhide
T
Koyama
Ryuichi
R
Uetake
Hisaka
H
Kawate
Shin-Ichi
S
Muto
Yoh-Ichi
Y
Tagawa
Shinichi
S
Miyagawa
Takayuki
T
Shindo
D053607:Adrenomedullin / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003080:Cold Temperature; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D053583:Interleukin-1beta; D015850:Interleukin-6; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D053607:Adrenomedullin