The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.

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-Stem cell-specific proteins and regulatory pathways that determine self-renewal and differentiation have become of fundamental importance in understanding regenerative and reparative processes in the myocardium. One such regulatory protein, named nucleostemin, has been studied in the context of stem cells and several cancer cell lines, where expression is associated with proliferation and maintenance of a primitive cellular phenotype. We find nucleostemin is present in young myocardium and is also induced following cardiomyopathic injury. Nucleostemin expression in cardiomyocytes is induced by fibroblast growth factor-2 and accumulates in response to Pim-1 kinase activity. Cardiac stem cells also express nucleostemin that is diminished in response to commitment to a differentiated phenotype. Overexpression of nucleostemin in cultured cardiac stem cells increases proliferation while preserving telomere length, providing a mechanistic basis for potential actions of nucleostemin in promotion of cell survival and proliferation as seen in other cell types. (Circ Res. 2008;103:89-97.)Key Words: nucleostemin Ⅲ cardioprotection Ⅲ cardiomyocytes Ⅲ stem cells Ⅲ Pim-1 Ⅲ telomerase C ellular-based myocardial regeneration depends on tightly regulated signaling cascades that control survival and proliferation. In the case of stem cell populations, these signaling pathways have been predominantly defined by decades of study in hematopoietic 1-4 and developmental contexts. [5][6][7] The relatively recent advent of myocardial adult stem cells and their distinctive characteristics has prompted reexamination of the operational definition of "stem cells" and "stemness." 8,9 The traditional view of stem cell behavior as derived from classic lineage studies may not appropriately reflect the biology of stem cells in tissues characterized by slow cellular turnover such as the myocardium. For example, activation of signaling typically associated with regulation of proliferation and survival in stem cells is also observed in combination with partial or fully committed cellular phenotypes following tissue injury. 10 -12 These revelations have prompted dissolution of long-standing assertions related to "stem cell-associated" signaling, now viewed as regulation of tissue repair and regeneration or, in some, cases oncogenic transformation. [13][14][15][16] Nucleostemin is found at high levels in various stem cells and human cancers, 17 where it has been associated with maintenance of proliferation. [17][18][19][20] Expression of nucleostemin drops precipitously during differentiation 21,22 and genetic deletion of nucleostemin results in embryonic lethality at approximately day 4 postcoitum with blastocysts comprised of cells that fail to enter S phase. 23 Similar arrest in G 0 /G 1 phase of cell cycle was observed in HeLa cells if nucleostemin was eliminated by RNA interference. 20 Nucleostemin has been purported to mediate cellular dedifferentiation and regenerative processes in newts. 24 Although the molecular basis of nucleostem...

The phosphoinositide-3-kinase (PI3K) / phosphoinositide dependent kinase 1 (PDK1) signaling pathway exerts cardioprotective effects in the myocardium through activation of key proteins including Akt. Activated Akt accumulates in nuclei of cardiomyocytes suggesting that biologically relevant targets are located in that subcellular compartment. Nuclear Akt activity could be potentiated in both intensity and duration by the presence of a nuclear-associated PI3K / PDK1 signaling cascade as has been described in other non-myocyte cell types. PI3K / PDK1 distribution was determined in vitro and in vivo by immunostaining and nuclear extraction of cultured rat neonatal cardiomyocytes or transgenic mouse hearts. Results show that PI3K and PDK1 are present at a basal level in cardiomyocytes nuclei and that cardioprotective stimulation with atrial natriuretic peptide (ANP) increases their nuclear localization. In comparison, overexpression of nuclear-targeted Akt does not mediate increased translocation of either PI3K or PDK1 indicating that accumulation of Akt does not drive PI3K or PDK1 into the nuclear compartment. Furthermore, PI3K and phospho-Akt 473 show parallel temporal accumulation in the nucleus following (MI) infarction challenge. These findings demonstrate the presence of a dynamically regulated nuclear-associated signaling cascade involving PI3K and PDK that presumably influences nuclear Akt activation.

No abstract

In the version of this article initially published, the meanings of the error bars in the figures and supplementary figures and the error values given in Supplementary Table 2 were not stated. They represent the standard error of the mean in all cases except Supplementary Figure 5, where they represent the standard deviation. The error has been corrected in the supplementary information file and in the PDF version of the article.

Case Presentation: A 24-year-old pregnant female presented to the emergency department with lower abdominal cramping and vaginal bleeding. A point-of-care ultrasound demonstrated a calcified yolk sac. Discussion: When identified, calcification of the yolk sac in the first trimester is a sign of fetal demise. It is important for an emergency physician to be aware of the various signs and findings on point-of-care ultrasound and be familiar with the management of these pathologies.