PLCδ1 Protein Rescues Ischemia-reperfused Heart by the Regulation of Calcium Homeostasis |
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| Authors: | Soyeon Lim Woochul Chang Min-Ji Cha Byeong-Wook Song Onju Ham Se-Yeon Lee Changyoun Lee Jun-Hee Park Sang-Kyou Lee Yangsoo Jang Ki-Chul Hwang |
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| Institution: | 1. Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, Seoul, Republic of Korea;2. Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea;3. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea;4. Institute of Catholic Integrative Medicine, Incheon St. Mary''s Hospital, The Catholic University of Korea College of Medicine, Incheon, Republic of Korea;5. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea;6. Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea;7. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea;8. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea |
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| Abstract: | Myocardial Ca2+ 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 Ca2+ homeostasis in various types of cells. Here, we investigated the protective role of PLCδ1 against myocardial I/R injury through the regulation of Ca2+ 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 Ca2+ 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. |
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