Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells

Sauer, Heinrich; Neukirchen, Wolfgang; Rahimi, Gohar; Grünheck, Frank; Hescheler, Jürgen; Wartenberg, Maria

doi:10.1016/j.yexcr.2003.10.032

Cited by 76 publications

(65 citation statements)

References 36 publications

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“…The progressive increase in cyclin D1 and D3 levels may be a response to increased cell proliferation resulting from increased cell damage and death under conditions of CuZnSOD deficiency. Conversely, increased cyclin D1 and D3 may be responsive to elevated ROS, which stimulate cell proliferation (Liu and Liu, 2004;Sauer et al, 2004). The increase in ROS may have caused an increase in cell cycle progression and subsequently contributed to hepatocarcinogenesis in Sod1À/À mice.…”

Section: Discussionmentioning

confidence: 99%

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

et al. 2004

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Mice deficient in CuZn superoxide dismutase (CuZn-SOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1À/À mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1À/À and age-matched þ / þ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1À/À mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.

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Section: Discussionmentioning

confidence: 99%

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

et al. 2004

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“…Interestingly, a recent publication reports that NADPH-dependent ROS can also play a role in ESC during cardiotrophin-1-induced cardiac proliferation (Sauer et al, 2004;Ateghang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Other pathways linking ROS to cardiac development include PI3-kinase as its inhibition impairs ROS production and, as a consequence, cardiac differentiation (Sauer et al, 2000). Signal transduction cascades induced by the cardiogenic cytokine cardiotrophin-1 via Jak/STAT also appear to depend on ROS (Sauer et al, 2004;Ateghang et al, 2006).In the mouse embryonal carcinoma cell model, activation of p38 MAPK has been shown to be necessary for cardiac differentiation (Davidson and Morange, 2000;Eriksson and Leppa, 2002). However, the precise role and, in particular, the source of ROS in cardiac differentiation remains to be elucidated.…”

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confidence: 99%

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The NADPH Oxidase NOX4 Drives Cardiac Differentiation: Role in Regulating Cardiac Transcription Factors and MAP Kinase Activation

Li¹,

Stouffs²,

Serrander³

et al. 2006

MBoC

262

203

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Reactive oxygen species (ROS) generated by the NOX family of NADPH oxidases have been described to act as second messengers regulating cell growth and differentiation. However, such a function has hitherto not been convincingly demonstrated. We investigated the role of NOX-derived ROS in cardiac differentiation using mouse embryonic stem cells. ROS scavengers prevented the appearance of spontaneously beating cardiac cells within embryoid bodies. Downregulation of NOX4, the major NOX isoform present during early stages of differentiation, suppressed cardiogenesis. This was rescued by a pulse of low concentrations of hydrogen peroxide 4 d before spontaneous beating appears. Mechanisms of ROS-dependent signaling included p38 mitogen-activated protein kinase (MAPK) activation and nuclear translocation of the cardiac transcription factor myocyte enhancer factor 2C (MEF2C). Our results provide first molecular evidence that the NOX family of NADPH oxidases regulate vertebrate developmental processes. INTRODUCTIONReactive oxygen species (ROS) are generated either in a nonregulated manner as side products of several enzymatic systems (e.g., cyclooxygenases, nitric oxide [NO] synthases, mitochondrial cytochromes) or in a regulated way as main products of superoxide producing enzymes, the NADPH oxidases. In the mouse, the family of NADPH oxidases includes NOX1, NOX2 (gp91 phox ), NOX3, and NOX4.Excessive cellular generation of ROS, such as superoxide anions (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ), is potentially destructive and is used by phagocytes to kill invading microorganisms. Under normal conditions, scavenging mechanisms (e.g., superoxide dismutase, catalase, glutathioneglutathione peroxidase system) remove excessive amounts of ROS. Under stress conditions, however, the production of ROS may exceed the reducing capacity of the cell and damage cellular functions. Small amounts of ROS, on the other hand, can function as intracellular second messengers and activate signaling cascades involved in growth and differentiation of many cell types (for review see Rhee, 1999;Laloi et al., 2004). For example, the MAP kinase-signaling pathway is sensitive to ROS (Torres and Forman, 2003). Moreover, distinct signaling pathways have differential sensitivity to oxidative stress, leading to dose-dependent effect on, for example, cardiomyocytes on which ROS can induce hypertrophy or apoptosis (Kwon et al., 2003). Transcription factors such as NF-B, p53, and AP-1 are redox-sensitive and can be directly modified by ROS, providing a link with the control of gene expression (Morel and Barouki, 1999).Cardiac differentiation can be studied by differentiating mouse embryonic stem cells (ESC) into embryoid bodies (EB), where the appearance of spontaneously beating cardiomyocytes is observed after 7-8 d of culture. This system thus provides a unique experimental model to study the role of ROS and ROS-generating enzymes in the regulation of cardiomyocyte growth and differentiation in vitro. Previous reports have shown a link between ROS and...

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“…For example, a number of studies have implicated signaling of BMP and Wnt family members in cardiomyogenic differentiation of ES cells (Winnier et al 1995;Czyz and Wobus 2001;Behfar et al 2002;Kawai et al 2004;Terami et al 2004). In addition, signaling through the FGF (Dell'Era et al 2003;Kawai et al 2004), IGF-II (Morali et al 2000), Crypto (Parisi et al 2003), PDGFBB (Sachinidis et al 2003), CT-1 (Sauer et al 2004), TGF-beta (Behfar et al 2002), and dynorphin B (Ventura et al 2003) pathways enhanced cardiomyogenesis during EB differentiation. Perhaps not unexpectedly, cytokine/growth factor treatments were occasionally observed to promote cardiomyogenic differentiation via rather indirect mechanisms.…”

Section: Identification Of Factors That Enhance Cardiomyogenic Differmentioning

confidence: 99%

Cardiac Repair by Embryonic Stem-Derived Cells

Rubart

Field

2006

Stem Cells

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Cell transplantation approaches offer the potential to promote regenerative growth of diseased hearts. It is well established that donor cardiomyocytes stably engraft into recipient hearts when injected directly into the myocardial wall. Moreover, the transplanted donor cardiomyocytes participate in a functional syncytium with the host myocardium. Thus, transplantation of donor cardiomyocytes resulted in at least partial restoration of lost muscle mass. It is also well established that embryonic stem (ES) cells differentiate into cells of ecto-, endo-, and mesodermal lineages when cultured under appropriate conditions in vitro. Robust cardiomyogenic differentiation was frequently observed in spontaneously differentiating ES cultures. Cellular, molecular and physiologic analyses indicated that ES-derived cells were bona fide cardiomyocytes, with in vitro characteristics typical for cells obtained from early stages of cardiac development. Thus, ES-derived cardiomyocytes constitute a viable source of donor cells for cell transplantation therapies.

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Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells

Cited by 76 publications

References 36 publications

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

The NADPH Oxidase NOX4 Drives Cardiac Differentiation: Role in Regulating Cardiac Transcription Factors and MAP Kinase Activation

Cardiac Repair by Embryonic Stem-Derived Cells

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