PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis

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

doi:10.1038/mt.2014.46

PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis

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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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.

Original language	English
Pages (from-to)	1110-1121
Number of pages	12
Journal	Molecular Therapy
Volume	22
Issue number	6
DOIs	https://doi.org/10.1038/mt.2014.46
Publication status	Published - 2014 Jun

Bibliographical note

Funding Information:
The authors appreciate comments and helpful feedbacks from several experts including Robert M. Graham, Sue Goo Rhee, and Im Mie-Jae. We also thank Dong-Su Jang, a research assistant in the Department of Anatomy at Yonsei University College of Medicine in Seoul, Korea, for his help with the figures. This research was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (MEST) (2011-0019243, 2011-0019254), a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A120478), and a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (HI08C2149). All authors have declared that there are no conflicts of interests.

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1038/mt.2014.46

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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.",

author = "Soyeon Lim and Woochul Chang and Cha, {Min Ji} and Song, {Byeong Wook} and Onju Ham and Lee, {Se Yeon} and Changyoun Lee and Park, {Jun Hee} and Lee, {Sang Kyou} and Yangsoo Jang and Hwang, {Ki Chul}",

note = "Funding Information: The authors appreciate comments and helpful feedbacks from several experts including Robert M. Graham, Sue Goo Rhee, and Im Mie-Jae. We also thank Dong-Su Jang, a research assistant in the Department of Anatomy at Yonsei University College of Medicine in Seoul, Korea, for his help with the figures. This research was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (MEST) (2011-0019243, 2011-0019254), a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A120478), and a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (HI08C2149). All authors have declared that there are no conflicts of interests.",

year = "2014",

month = jun,

doi = "10.1038/mt.2014.46",

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volume = "22",

pages = "1110--1121",

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T1 - PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis

AU - Lim, Soyeon

AU - Chang, Woochul

AU - Cha, Min Ji

AU - Song, Byeong Wook

AU - Ham, Onju

AU - Lee, Se Yeon

AU - Lee, Changyoun

AU - Park, Jun Hee

AU - Lee, Sang Kyou

AU - Jang, Yangsoo

AU - Hwang, Ki Chul

N1 - Funding Information: The authors appreciate comments and helpful feedbacks from several experts including Robert M. Graham, Sue Goo Rhee, and Im Mie-Jae. We also thank Dong-Su Jang, a research assistant in the Department of Anatomy at Yonsei University College of Medicine in Seoul, Korea, for his help with the figures. This research was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (MEST) (2011-0019243, 2011-0019254), a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A120478), and a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (HI08C2149). All authors have declared that there are no conflicts of interests.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

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PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis

Abstract

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