The Pro-angiogenic Cytokine Pleiotrophin Potentiates Cardiomyocyte Apoptosis through Inhibition of Endogenous AKT/PKB Activity

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 GSK3␤ phosphorylation. Adenoviral expression of constitutively active AKT and lithium chloride-mediated inhibition of GSK3␤ 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.

The role of pleiotrophin in bone repair

“…PTN shows both cytoplasmic (red arrows) and nuclear (black arrows) localization (brown staining), with the latter being dominant. Although there is no known physiological significance for the nuclear localization of PTN, it has been also observed in endothelial and glioma cells [78], cardiomyocytes [91] and osteoarthritic chondrocytes [9]. (For interpretation of the references to color in this text, the reader is referred to the web version of the article.)…”

A minimally invasive endovascular rabbit model for experimental induction of progressive myocardial hypertrophy

“…Although involvement of PTN in cardiac hypertrophy has not been extensively studied, our data are in line with a previous observation that PTN is increased in cardiac hypertrophy observed in atrial natriuretic peptide-null mice demonstrated at baseline or after transverse aortic constriction. 27 PTN has been also shown to potentiate cardiomyocyte cell death in response to proapoptotic stress in damaged heart that may be critical to myocardial injury repair 28 and PTN gene delivery leads to functional benefit in ischemic myocardium. 29 It is possible that PTN expression is affected by and/ or compensates decreased expression of VEGF or plays an independent role that requires further studies to be identified.…”

Heparin-Binding Protein Pleiotrophin: An Important player in the Angiogenic Process

“…Promoter analysis revealed the existence of a CAAT box, no apparent TATA box, a serum response element, four MyoD, two putative AP1 and one GT1 binding sites in the distal 5' flanking region [12]. Moreover, it has been shown that hypoxia [13,14], PDGF [13] and cAMP [15] increase PTN expression, although the mechanisms involved are not known. It has been shown that PTN promoter contains a response element to HOXA5, which leads to increased PTN production [16].…”

“…It is also important for clonal growth and long-term expansion of human embryonic stem cells [19]. More recently it has been shown to potentiate cardiomyocyte apoptosis and foster cardiomyocyte programmed cell death in response to proapoptotic stress, which may be critical to myocardial injury repair [14].…”