Neural cell adhesion molecule is a cardioprotective factor up-regulated by metabolic stress.
Screening for cell surface proteins up-regulated under stress conditions may lead to the identification of new therapeutic targets. To search for genes whose expression was enhanced by treatment with oligomycin, a mitochondrial-F(0)F(1) ATP synthase inhibitor, signal sequence trapping was performed in H9C2 rat cardiac myoblasts. One of the genes identified was that for neural cell adhesion molecule (NCAM, CD56), a major regulator of development, cell survival, migration, and neurite outgrowth in the nervous system. Immunohistochemical analyses in a mouse myocardial infarction model revealed that NCAM was strongly expressed in residual cardiac myocytes in the infarcted region. Increased expression of NCAM was also found during the remodeling period in a rat model of hypertension-induced heart failure. Lentivirus-mediated knockdown of NCAM decreased the cell growth and survival following oligomycin treatment in H9C2 cells. In primary rat neonatal cardiac myocytes, NCAM was also found to be up-regulated and played a protective role following oligomycin treatment. Analyses of downstream signaling revealed that knockdown of NCAM significantly decreased the basal AKT phosphorylation level. In contrast, NCAM mimetic peptide P2d activated AKT and significantly reduced oligomycin-induced cardiomyocyte death, which was abolished by treatment with the PI3K inhibitor LY-294002 as well as overexpression of the dominant-negative AKT mutant. These findings demonstrate that NCAM is a cardioprotective factor up-regulated under metabolic stress in cardiomyocytes and augmentation of this signal improved survival.
Department of Cardiovascular Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Kazuya
K
Nagao
Koh
K
Ono
Yoshitaka
Y
Iwanaga
Yodo
Y
Tamaki
Yoji
Y
Kojima
Takahiro
T
Horie
Hitoo
H
Nishi
Minako
M
Kinoshita
Yasuhide
Y
Kuwabara
Koji
K
Hasegawa
Toru
T
Kita
Takeshi
T
Kimura
D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D051381:Rats; D015854:Up-Regulation
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D019006:Neural Cell Adhesion Molecules; D009840:Oligomycins; D006180:Proton-Translocating ATPases