Abstract-Endoplasmic reticulum (ER) stresses that reduce ER protein folding activate the unfolded protein response (UPR). One effector of the UPR is the transcription factor X-box binding protein-1 (XBP1), which is expressed on ER stress-mediated splicing of the XBP1 mRNA. XBP1 induces certain ER-targeted proteins, eg, glucose-regulated protein 78 (GRP78), that help resolve the ER stress and foster cell survival. In this study, we determined whether hypoxia can activate the UPR in the cardiac context. Neonatal rat ventricular myocyte cultures subjected to hypoxia (16 hours) exhibited increased XBP1 mRNA splicing, XBP1 protein expression, GRP78 promoter activation, and GRP78 protein levels; however, the levels of these UPR markers declined during reoxygenation, suggesting that the UPR is activated during hypoxia but not during reoxygenation. When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased. Confocal immunocytofluorescence demonstrated that hypoxia induced GRP78 in neonatal rat and isolated adult mouse ventricular myocytes. Moreover, mouse hearts subjected to in vivo myocardial infarction exhibited increased GRP78 expression in cardiac myocytes near the infarct, but not in healthy cells distal to the infarct. These results indicate that hypoxia activates the UPR in cardiac myocytes and that XBP1-inducible proteins may contribute to protecting the myocardium during hypoxic stress.
Abstract-The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades.
STEM CELLS 2008;26:1315-1324 Disclosure of potential conflicts of interest is found at the end of this article.
Abstract-Activation of Akt is associated with enhanced cell cycling and cellular proliferation in nonmyocytes, but this effect of nuclear Akt accumulation has not been explored in the context of the myocardium. Cardiac-specific expression of nuclear-targeted Akt (Akt/nuc) in transgenics prolongs postnatal cell cycling as evidenced by increased numbers of Ki67 ϩ cardiomyocytes at 2 to 3 weeks after birth. Similarly, nuclear-targeting of Akt promotes expansion of the presumptive cardiac progenitor cell population as assessed by immunolabeling for c-kit in combination with myocyte-specific markers Nkx 2.5 or MEF 2C. Increases in pro-proliferative cytokines, including tumor-necrosis superfamily 8, interleukin-17e, and hepatocyte growth factor, were found in nuclear-targeted Akt myocardial samples. Concurrent signaling mediated by paracrine factors downstream of Akt/nuc expression may be responsible for phenotypic effects of nuclear-targeted Akt in the myocardium, including enhanced cell proliferation and expansion of the stem cell population. Key Words: PKB/Akt Ⅲ cardiac stem cell Ⅲ proliferation Ⅲ cytokines Ⅲ postnatal growth P ostnatal growth of the myocardium results from combined actions of cellular proliferation and hypertrophy. Both processes are downregulated as the myocardium achieves structural and functional characteristics of the adult heart. Mechanisms determining the ultimate size and cellular density of the normal adult heart remain obscure, but it is clear that signaling to regulate growth and proliferation influences the outcome. Specifically, overexpression of insulin-like growth factor 1 (IGF-1) in the postnatal heart by cardiac-specific transgenesis results in hyperplastic growth without myocyte hypertrophy. 1 In contrast, postnatal activation of various hypertrophic signaling cascades provokes cellular hypertrophy and substantial increases in cardiac mass. 2,3 A nodal signaling kinase linked to both hyperplasia and hypertrophy of cardiomyocytes is Akt, a serine/threonine kinase with potent antiapoptotic action in vitro and in vivo. 4 Akt is activated by multiple cardioprotective stimuli under physiological conditions, but Akt activation in the myocardium of genetically engineered mice has predominantly been associated with cardiomyopathic hypertrophy and transition to heart failure. 5-7 These apparently paradoxical findings were reconciled by our recent reports that nuclear-targeting of Akt kinase in transgenic mice produces a heart exhibiting phenotypic characteristics of hyperplasia without hypertrophy and resistance to apoptotic stimuli. 8,9 These properties, also evident in the hearts of transgenic mice possessing cardiac-specific expression of IGF-1, suggest that Akt localization in the nucleus rather than cytoplasmic accumulation is an important aspect of appropriate biological activity.Akt is associated with the promotion of cellular proliferation in many noncardiac cell types including oncogenic transformation. 10 -12 The commonality of cardiomyocyte hyperplasia without hypertrophy in tr...
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