title: Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment Through the Action on AMPK-PGC1α Signaling in Heart Failure.
abstract: Data are limited on the mechanisms underlying memory impairment in heart failure (HF). We hypothesized that angiotensin II (Ang II) may determine the fate of adult hippocampal neural stem cells (HCNs), a cause of memory impairment in HF. HCNs with neurogenesis potential were isolated and cultured from adult rat hippocampi. Ang II decreased HCN proliferation in dose- and time-dependent manners. Moreover, Ang II treatment (1 µM) for 48 hours induced apoptotic death, which was attenuated by pretreatment with Ang II receptor blockers (ARBs). Ang II increased mitochondrial reactive oxygen species (ROS) levels, which was related to mitochondrial morphological changes and functional impairment. Moreover, ROS activated the AMP-activated protein kinase (AMPK) and consequent peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression, causing cell apoptosis. In the HF rat model induced by left anterior descending artery ligation, ARB ameliorated the spatial memory ability which decreased 10 weeks after ischemia. In addition, neuronal cell death, especially of newly born mature neurons, was observed in HF rat hippocampi. ARB decreased cell death and promoted the survival of newly born neural precursor cells and mature neurons. In conclusion, Ang II caused HCN apoptosis through mitochondrial ROS formation and subsequent AMPK-PGC1α signaling. ARB improved learning and memory behaviors impaired by neuronal cell death in the HF animal model. These findings suggest that HCN is one treatment target for memory impairment in HF and that ARBs have additional benefits in HF combined with memory impairment. Stem Cells Translational Medicine 2017;6:1491-1503.
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Min-Seok
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Geun-Hee
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyunghee University, Seoul, Korea.
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Byoung-Wook
authors.initials: BW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hae Yun
authors.initials: HY
authors.lastname: Nam
authors.affiliation: Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyunghee University, Seoul, Korea.
authors.forename: U-Cheol
authors.initials: UC
authors.lastname: Sim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Suk-Jung
authors.initials: SJ
authors.lastname: Choo
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea.
authors.forename: Seong-Woon
authors.initials: SW
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jae-Joong
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyunghee University, Seoul, Korea.
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Kim Kwon
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seong
authors.initials: S
authors.lastname: Who Kim
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D005260:Female; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D000804:Angiotensin II; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases
keywords: Angiotensin; Cardiac; Cell biology; Neural stem cell