Protective effect of adrenomedullin in mannitol-induced apoptosis.
Mannitol therapy is widely used for reducing brain edema, and ischemic brain swelling. However, mannitol at clinical concentrations induces apoptosis in endothelial cells. Because apoptosis may be a pathogenic mechanism in vascular injury, antiapoptotic agents may have a protective role in mannitol-induced apoptosis. In this study, we examined whether adrenomedullin (AM) prevents mannitol-induced apoptosis and also evaluated the associated signaling pathway of AM in human umbilical vein endothelial cells. AM prevented mannitol-induced apoptosis in a dose-dependent manner. Pretreatment with wortmannin blocked the AM-induced antiapoptotic effect. AM stimulated Akt at Ser473, and wortmannin inhibited the AM-induced Akt phosphorylation. These findings indicate that phosphatidylinositol 3'-kinase/Akt pathway transmits the survival signal from AM. The potency of antiapoptotic effect of AM is stronger than that of vascular endothelial growth factor and angiopoietin-1 in mannitol-induced apoptosis. AM can have a protective role not only in umbilical vein, but also in pulmonary, coronary, and aortic endothelial cells. These findings indicate that AM has a potent protective role in mannitol-induced apoptosis, through phosphatidylinositol 3'-kinase/Akt pathway. Therefore, pretreatment with AM might help to maintain normal endothelial integrity during systemic mannitol therapy.
Kim
Won
W
Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Chonju, Republic of Korea.
Moon
Sang-Ok
SO
Sung
Mi Jeong
MJ
Kim
Sung Hoon
SH
Lee
Sik
S
Kim
Hyung Jin
HJ
Koh
Gou Young
GY
Park
Sung Kwang
SK
D053607:Adrenomedullin; D000730:Androstadienes / Q000494:pharmacology; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D042683:Angiopoietin-1; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004347:Drug Interactions; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D008353:Mannitol / Q000008:administration & dosage / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077191:Wortmannin
D053607:Adrenomedullin; D000730:Androstadienes; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008353:Mannitol; D008562:Membrane Glycoproteins; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077191:Wortmannin; C467630:ANGPT1 protein, human; C467629:Angpt1 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat