A Novel Atypical PKC-Iota Inhibitor, Echinochrome A, Enhances Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells
Hyoung Kyu Kim,
Sung Woo Cho,
Hye Jin Heo,
Seung Hun Jeong,
Min Kim,
Kyung Soo Ko,
Byoung Doo Rhee,
Natalia P. Mishchenko,
Elena A. Vasileva,
Sergey A. Fedoreyev,
Valentin A. Stonik,
Jin Han
Affiliations
Hyoung Kyu Kim
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Sung Woo Cho
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Hye Jin Heo
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Seung Hun Jeong
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Min Kim
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Kyung Soo Ko
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Byoung Doo Rhee
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Natalia P. Mishchenko
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia
Elena A. Vasileva
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia
Sergey A. Fedoreyev
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia
Valentin A. Stonik
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia
Jin Han
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan 47392, Korea
Echinochrome A (EchA) is a marine bioproduct extracted from sea urchins having antioxidant, antimicrobial, anti-inflammatory, and chelating effects, and is the active component of the clinical drug histochrome. We investigated the potential use of Ech A for inducing cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). We also assessed the effects of Ech A on mitochondrial mass, inner membrane potential (Δψm), reactive oxygen species generation, and levels of Ca2+. To identify the direct target of Ech A, we performed in vitro kinase activity and surface plasmon resonance binding assays. Ech A dose-dependently enhanced cardiomyocyte differentiation with higher beating rates. Ech A (50 μM) increased the mitochondrial mass and membrane potential but did not alter the mitochondrial superoxide and Ca2+ levels. The in vitro kinase activity of the atypical protein kinase C-iota (PKCι) was significantly decreased by 50 μM of Ech A with an IC50 for PKCι activity of 107 μM. Computational protein-ligand docking simulation results suggested the direct binding of Ech A to PKCι, and surface plasmon resonance confirmed the direct binding with a low KD of 6.3 nM. Therefore, Ech A is a potential drug for enhancing cardiomyocyte differentiation from mESCs through direct binding to PKCι and inhibition of its activity.
