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 GSK3beta phosphorylation. Adenoviral expression of constitutively active AKT and lithium chloride-mediated inhibition of GSK3beta 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.
Highlights
Growth factors and cytokines have essential roles throughout embryonic and fetal development
This latter quantity is similar to that reported in human brain and gliomas, which have been reported to have some of the highest levels of PTN among adult human tissues [33]
We cannot determine the primary source of PTN, which could be either resident cells or infiltrates of inflammatory cells present in damaged myocardium, its distribution demonstrates that PTN is elevated in the peri-infarct myocardium and is in close proximity to contractile cells
Summary
Activation of the MAPK pathway by PTN inhibits programmed cell death in NIH3T3 cells, whereas activation of the PI3K pathway is generally believed to be protective. PTN does, seem to promote cardiac vascularization following ischemia [26] and increase bromodeoxyuridine incorporation into mouse heart cells in vivo [27]. These latter results led to the suggestion that injection of recombinant PTN might represent a potential therapeutic agent that could initiate new vessel formation in damaged myocardium, even though its effects on CMs have not been rigorously investigated. That PTN is released from CMs in response to cell stress and can potentiate CM apoptosis through inhibition of AKT signaling
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