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 languageEnglish
Pages (from-to)1110-1121
Number of pages12
JournalMolecular Therapy
Volume22
Issue number6
DOIs
Publication statusPublished - 2014 Jun

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Lim, S., Chang, W., Cha, M. J., Song, B. W., Ham, O., Lee, S. Y., Lee, C., Park, J. H., Lee, S. K., Jang, Y., & Hwang, K. C. (2014). PLCδ1 protein rescues ischemia-reperfused heart by the regulation of calcium homeostasis. Molecular Therapy, 22(6), 1110-1121. https://doi.org/10.1038/mt.2014.46