The pro-angiogenic cytokine pleiotrophin potentiates cardiomyocyte apoptosis through inhibition of endogenous AKT/PKB activity

Jinliang Li, Hong Wei, Alan Chesley, Chanil Moon, Melissa Krawczyk, Maria Volkova, Bruce Ziman, Kenneth B. Margulies, Mark Talan, Michael T. Crow, Kenneth R. Boheler

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Pleiotrophin is a development-regulated cytokine and growth factor that can promote angiogenesis, cell proliferation, or differentiation, and it has been reported to have neovasculogenic effects in damaged heart. Developmentally, it is prominently expressed in fetal and neonatal hearts, but it is minimally expressed in normal adult heart. Conversely, we show in a rat model of myocardial infarction and in human dilated cardiomyopathy that pleiotrophin is markedly up-regulated. To elucidate the effects of pleiotrophin on cardiac contractile cells, we employed primary cultures of rat neonatal and adult cardiomyocytes. We show that pleiotrophin is released from cardiomyocytes in vitro in response to hypoxia and that the addition of recombinant pleiotrophin promotes caspase-mediated genomic DNA fragmentation in a dose- and time-dependent manner. Functionally, it potentiates the apoptotic response of neonatal cardiomyocytes to hypoxic stress and to ultraviolet irradiation and of adult cardiomyocytes to hypoxia-reoxygenation. Moreover, UV-induced apoptosis in neonatal cardiomyocytes can be partially inhibited by small interfering RNA-mediated knockdown of endogenous pleiotrophin. Mechanistically, pleiotrophin antagonizes IGF-1 associated Ser-473 phosphorylation of AKT/PKB, and it concomitantly decreases both BAD and GSK3β phosphorylation. Adenoviral expression of constitutively active AKT and lithium chloride-mediated inhibition of GSK3β reduce the potentiated programmed cell death elicited by pleiotrophin. These latter data indicate that pleiotrophin potentiates cardiomyocyte cell death, at least partially, through inhibition of AKT signaling. In conclusion, we have uncovered a novel function for pleiotrophin on heart cells following injury. It fosters cardiomyocyte programmed cell death in response to pro-apoptotic stress, which may be critical to myocardial injury repair.

Original languageEnglish (US)
Pages (from-to)34984-34993
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number48
DOIs
StatePublished - Nov 30 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Li, J., Wei, H., Chesley, A., Moon, C., Krawczyk, M., Volkova, M., Ziman, B., Margulies, K. B., Talan, M., Crow, M. T., & Boheler, K. R. (2007). The pro-angiogenic cytokine pleiotrophin potentiates cardiomyocyte apoptosis through inhibition of endogenous AKT/PKB activity. Journal of Biological Chemistry, 282(48), 34984-34993. https://doi.org/10.1074/jbc.M703513200