Sizing up the heart: development redux in disease

Olson, Eric N.; Schneider, Michael

doi:10.1101/gad.1110103

Cited by 359 publications

(299 citation statements)

References 213 publications

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“…Molecules that mediate cardiogenesis are of particular interest because of their potential use for cardiac regeneration 4,5 . Previous studies have shown that soluble growth factors such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Wnts and Wnt inhibitors mediate the tissue interactions that are crucial for cardiomyocyte specification 3,4 . We proposed that there might be additional soluble factors that modulate cardiac development and/or cardiomyocyte differentiation.…”

mentioning

confidence: 99%

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IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Zhu

Shiojima

Ito

et al. 2008

Nature

201

165

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Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs) 1 . Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown 1,2 . Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, lowdensity lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.The heart is the first organ to form during embryogenesis, and abnormalities in this process result in congenital heart diseases, the most common cause of birth defects in humans 3 . Molecules that mediate cardiogenesis are of particular interest because of their potential use for cardiac regeneration 4,5 . Previous studies have shown that soluble growth factors such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Wnts and Wnt inhibitors mediate the tissue interactions that are crucial for cardiomyocyte specification 3,4 . We proposed that there might be additional soluble factors that modulate cardiac development and/or cardiomyocyte differentiation.P19CL6 cells differentiate into cardiomyocytes with high efficiency in the presence of 1% dimethylsulphoxide (DMSO) 6 . We cultured P19CL6 cells with culture media conditioned by various cell types in the absence of DMSO, and screened the cardiogenic activity of the conditioned media. The extent of cardiomyocyte differentiation was assessed by the immunostaining with MF20 monoclonal antibody that recognizes sarcomeric myosin heavy chain (MHC). Among the several cell types tested, culture media conditioned by a murine stromal cell line OP9 induced cardiomyocyte differentiation of P19CL6 cells without DMSO treatment (Fig. 1a, left and middle panels). Increased MF20-positive area was accompanied by the induction of cardiac marker genes such as aMHC, Nkx2.5 and GATA-4, and by the increased protein levels of cardiac troponin T (cTnT) (Fig. 1a, right panel). In contrast, culture media conditioned by COS7 cells, mouse embryonic fibroblasts, NIH3T3 cells, HeLa cells, END2 cells (visceral endoderm-like cells), neonatal rat cardiomyocytes and neonatal rat cardiac fibroblasts did not induce cardiomyocyte differentiation of P19CL6 cells in the absence of DMSO (Fig. 1a and data not shown). From these observations, we p...

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confidence: 99%

“…The heart is the first organ to form during embryogenesis, and abnormalities in this process result in congenital heart diseases, the most common cause of birth defects in humans 3 . Molecules that mediate cardiogenesis are of particular interest because of their potential use for cardiac regeneration 4,5 .…”

mentioning

confidence: 99%

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Zhu

Shiojima

Ito

et al. 2008

Nature

201

165

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“…MAPK signaling pathways are also interconnected at multiple levels with calcium-dependent kinases and calcineurin (21). The details of these pathways have been reviewed elsewhere (6)(7)(8)(9)22). β-Adrenergic agonists also influence cardiac growth and function through the generation of cAMP, which activates PKA and other downstream effectors (23).…”

Section: Transcriptional Remodeling Of the Hypertrophic And Failing Hmentioning

confidence: 99%

“…Cardiac hypertrophy and failure are accompanied by the reprogramming of cardiac gene expression and the activation of "fetal" cardiac genes, which encode proteins involved in contraction, calcium handling, and metabolism ( Figure 1) (6)(7)(8)(9). Such transcriptional reprogramming has been shown to correlate with loss of cardiac function and, conversely, improvement in cardiac function in response to drug therapy or implantation of a left ventricular assist device is accompanied by normalization of cardiac gene expression (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

McKinsey¹,

Olson²

2005

J. Clin. Invest.

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117

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In response to acute and chronic stresses, the heart frequently undergoes a remodeling process that is accompanied by myocyte hypertrophy, impaired contractility, and pump failure, often culminating in sudden death. The existence of redundant signaling pathways that trigger heart failure poses challenges for therapeutic intervention. Cardiac remodeling is associated with the activation of a pathological gene program that weakens cardiac performance. Thus, targeting the disease process at the level of gene expression represents a potentially powerful therapeutic approach. In this review, we describe strategies for normalizing gene expression in the failing heart with small molecules that control signal transduction pathways directed at transcription factors and associated chromatin-modifying enzymes.

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“…DNA synthesis, karyokinesis, and cytokinesis do not occur in rat cardiomyocytes three weeks after birth. [7][8][9][10][11] We have previously shown that cyclin D1 is induced by mitogenic stimuli, but its nuclear import is impaired in terminally differentiated cardiomyocytes. The expression of nuclear localizing signal (NLS)-tagged cyclin D1 (D1NLS) and CDK4 triggers the cell cycle, indicating that the impairment of nuclear expression of cyclin D1 is one of the barriers of the cell cycle …”

Section: Introductionmentioning

confidence: 99%

Differential regulation of cyclin D1 and D2 in protecting against cardiomyocyte proliferation

Tamamori‐Adachi¹,

Goto²,

Yamada³

et al. 2008

Cell Cycle

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Cardiomyocytes withdraw from cell cycle after terminal differentiation due in part to impaired nuclear import of cyclin D1. Thus, we have previously shown that expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and cyclin-dependent kinase 4 promotes cardiomyocyte proliferation both in vitro and in vivo. Here we show that cyclin D2 fails to stimulate cell cycle in cardiomocytes through a mechanism distinct from that of cyclin D1. We demonstrate that cyclin D2 can express in the nucleus much more efficiently than cyclin D1. Cyclin D2, however, was much less effective in activating CDK2 and cell proliferation than cyclin D1 when expressed transiently in the nucleus of cardiomyocytes using nuclear localization signals. Consistent with such an observation, CDK inhibitors p21 cip1 and p27 kip1 remained bound to CDK2 in cells expressing cyclin D2, whereas p21 and p27 were sequestered to cyclin D1 in cells expressing D1NLS. These data suggest that cyclin D2 has weaker affinities to the CDK inhibitors and therefore is less efficient in activating cell cycle than cyclin D1. According to such a notion, double knockdown of p21 and p27 in cells expressing D2NLS induced activation of CDK2/CDC2 and BrdU incorporation to levels similar to those in cells expressing D1NLS. Taken together, our data suggest that distinct mechanisms keep cyclin D1 and cyclin D2 from activating cell cycle in terminally differentiated cardiomyocytes.

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Sizing up the heart: development redux in disease

Cited by 359 publications

References 213 publications

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

Differential regulation of cyclin D1 and D2 in protecting against cardiomyocyte proliferation

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