title: Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury.
abstract: Pigment epithelium-derived factor (PEDF) is a multifunctional protein that exhibits anti-angiogenic, antitumor, anti-inflammatory, antioxidative, anti-atherogenic, and cardioprotective properties. While it was recently shown that PEDF expression is inhibited under low oxygen conditions, the functional role of PEDF in response to hypoxia/reoxygenation (H/R) remains unclear. The goal of this study was to therefore investigate the influence of PEDF on myocardial H/R injury. For these analyses, PEDF-specific small interfering RNA-expressing and PEDF-expressing lentivirus (PEDF-LV) vectors were utilized to knockdown or stably overexpress PEDF, respectively, within human cardiomyocytes (HCM) in vitro. We noted that reactive oxygen species (ROS) play important roles in the induction of cell death pathways, including apoptosis and autophagy in ischemic hearts. Our findings demonstrate that overexpression of PEDF resulted in a significant reduction in ROS production and attenuation of mitochondrial membrane potential depletion under H/R conditions. Furthermore, PEDF inhibited the activation of a two-step apoptotic pathway in which caspase-dependent (caspase-9 and caspase-3) and caspase-independent (apoptosis inducing factor and endonuclease G), which in turn cleaves several crucial substrates including the DNA repair enzyme poly (ADP-ribose) polymerase. Meanwhile, overexpression of PEDF also promoted autophagy, a process that is typically activated in response to H/R. Therefore, these findings suggest that PEDF plays a critical role in preventing H/R injury by modulating anti-oxidant and anti-apoptotic factors and promoting autophagy.
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 801, Taiwan.
authors.forename: Hsuan-Fu
authors.initials: HF
authors.lastname: Kuo
authors.affiliation: Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Po-Len
authors.initials: PL
authors.lastname: Liu
authors.affiliation: Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Inn-Wen
authors.initials: IW
authors.lastname: Chong
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan.|Department of Psychology, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan.
authors.forename: Yung-Hsiang
authors.identifier: 0000-0002-8756-5113
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Cardiovascular Center, Chi-Mei Hospital, Liouying, Tainan, 736, Taiwan.|Chia-Nan University of Pharmacy & Science, Tainan, 717, Taiwan.
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Ku
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 801, Taiwan.
authors.forename: Hsiu-Hua
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 801, Taiwan.
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Chiang
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 801, Taiwan.
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 801, Taiwan.
authors.forename: Huang-Jen
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 801, Taiwan.
authors.forename: Yen-Chieh
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
authors.forename: Chong-Chao
authors.initials: CC
authors.lastname: Hsieh
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015843:Serpins / Q000235:genetics* / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D020169:Caspases; D005136:Eye Proteins; D009414:Nerve Growth Factors; D017382:Reactive Oxygen Species; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor