Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway.
Indatraline is an antidepressive agent and a non-selective monoamine transporter inhibitor that blocks the reuptake of neurotransmitters (dopamine, serotonin, and norepinephrine). In this study, we report that indatraline induces autophagy via the suppression of mTOR/S6 kinase signaling. Autophagy induction was examined by a cell-based high content screening system using LysoTracker, which was followed by monodansylcadaverine staining and transmission electron microscope observation. Indatraline increased the number of EGFP-LC3 cells expressing autophagosomes in the cytoplasm. Conversion of LC3 was further validated by immunoblotting. Indatraline induced autophagy by affecting the AMPK/mTOR/S6K signaling axis and had no influence on the PI3K/AKT/ERK signaling. Moreover, indatraline induced autophagy in smooth muscle cells (SMCs); further, it exhibited therapeutic potential for restenosis by inhibiting SMC accumulation in a rat restenosis model. These results provide new insights into the role of monoamine transporters in autophagy regulation and identify indatraline as a novel agent for inducing autophagy.
Chemical Genomics Global Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Yoon Sun
YS
Cho
Chemical Genomics Global Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Chih-Na
CN
Yen
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USA.|Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.
Joong Sup
JS
Shim
Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
Dong Hoon
DH
Kang
Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
Sang Won
SW
Kang
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USA.
Jun O
JO
Liu
Chemical Genomics Global Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.|Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Ho Jeong
HJ
Kwon
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D023903:Coronary Restenosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008744:Methylamines / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D007189:Indans; D008744:Methylamines; C418119:indatraline; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases
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