title: PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis.
abstract: Myocardial Ca(2+) overload induced by ischemia/reperfusion (I/R) is a major element of myocardial dysfunction in heart failure. Phospholipase C (PLC) plays important roles in the regulation of the phosphoinositol pathway and Ca(2+) homeostasis in various types of cells. Here, we investigated the protective role of PLCδ1 against myocardial I/R injury through the regulation of Ca(2+) homeostasis. To investigate its role, PLCδ1 was fused to Hph1, a cell-permeable protein transduction domain (PTD), and treated into rat neonatal cardiomyocytes and rat hearts under respective hypoxia-reoxygenation (H/R) and ischemia-reperfusion conditions. Treatment with Hph1-PLCδ1 significantly inhibited intracellular Ca(2+) overload, reactive oxygen species generation, mitochondrial permeability transition pore opening, and mitochondrial membrane potential elevation in H/R neonatal cardiomyocytes, resulting in the inhibition of apoptosis. Intravenous injections of Hph1-PLCδ1 in rats with I/R-injured myocardium caused significant reductions in infarct size and apoptosis and also improved systolic and diastolic cardiac functioning. Furthermore, a small ions profile obtained using time-of-flight secondary ion mass spectrometry showed that treatment with Hph1-PLCδ1 leads to significant recovery of calcium-related ions toward normal levels in I/R-injured myocardium. These results suggest that Hph1-PLCδ1 may manifest as a promising cardioprotective drug due to its inhibition of the mitochondrial apoptotic pathway in cells suffering from I/R injury.
authors.affiliation: Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, Seoul, Republic of Korea.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea.
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Cha
authors.affiliation: Institute of Catholic Integrative Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Republic of Korea.
authors.forename: Byeong-Wook
authors.initials: BW
authors.lastname: Song
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Onju
authors.initials: O
authors.lastname: Ham
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Se-Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea.
authors.forename: Changyoun
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: kchwang@yuhs.ac.
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D007267:Injections; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051966:Phospholipase C gamma / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D063150:Polycomb Repressive Complex 1; D051966:Phospholipase C gamma; D002118:Calcium