Glycogen-Synthase Kinase3β/β-Catenin Axis Promotes Angiogenesis Through Activation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells

Skurk, Carsten; Maatz, Henrike; Rocnik, Edward; Bialik, Ann; Force, Thomas; Walsh, Kenneth

doi:10.1161/01.res.0000156273.30274.f7

Cited by 142 publications

(103 citation statements)

References 33 publications

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“…Thus, the PI3K/Akt pathway may promote cardiomyogenesis by maintaining the activity of Wnt signaling. Similar synergism between the PI3K/Akt pathway and the Wnt/␤-catenin pathway has been reported in PC12 cells (Fukumoto et al 2001) and endothelial cells (Skurk et al 2005b). Alternatively, Akt may promote cardiomyocyte differentiation by positively regulating the transcriptional activity of GATA-4 via inactivation of GSK3-␤ (Morisco et al 2001), or Akt may enhance BMP signaling-as shown in osteoblasts (Ghosh-Choudhury et al 2002)-that is essential for the expression of the cardiac transcription factor Nkx-2.5 (Olson and Schneider 2003).…”

Section: Regulation Of Cardiomyocyte Differentiation and Embryonic Hesupporting

confidence: 79%

Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway

Shiojima¹,

Walsh²

2006

Genes Dev.

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319

257

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Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinasedependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussed.Growth of the heart during embryonic development occurs primarily through proliferation of cardiac myocytes. However, cardiac myocytes withdraw from the cell cycle soon after birth, and subsequent growth of the heart during postnatal development is achieved predominantly through hypertrophy rather than hyperplasia of individual myocytes (Pasumarthi and Field 2002;Olson and Schneider 2003). In fact, there is almost a threefold increase in cardiac myocyte diameter in humans during development from infants to adults (Hudlicka and Brown 1996). Cardiac growth during normal postnatal development or the hypertrophy observed in trained athletes is referred to as "physiological," and it is characterized by normal or enhanced contractile function and normal architecture and organization of cardiac structure (Richey and Brown 1998). On the other hand, cardiac hypertrophy is also observed in patients with pathological conditions such as hypertension, myocardial infarction, and valvular heart diseases. This type of cardiac growth is called "pathological" hypertrophy, and is frequently associated with contractile dysfunction, interstitial fibrosis, and re-expression of fetal-type cardiac genes such as atrial natriuretic peptide and ␤-myosin heavy chain (Molkentin and Dorn 2001;Frey and Olson 2003). These data indicate that pathological cardiac hypertrophy is morphologically and molecularly distinct from physiological cardiac hypertrophy. The pathological form of cardiac hypertrophy is initially recognized as an adaptive response to increased external load, because increased wall stress induced by overload is attenuated by the increase in wall thickness. However, increased cardiac mass is clinically associated with increased morbidity and mortality (Levy et al. 1990), and a sustained overload eventually leads to contractile dysfunction and heart failure through poorly understood mechanisms (Molkentin and Dorn 2001;Frey and Olson 2003). In addition, hypertrophy of individual myocyte is a common feature of failing myocardium (Gerdes et al. 1992). Thus, pathological ...

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Section: Regulation Of Cardiomyocyte Differentiation and Embryonic Hesupporting

confidence: 79%

Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway

Shiojima¹,

Walsh²

2006

Genes Dev.

Self Cite

319

257

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“…Furthermore, embryonic aortic endothelial cells from Krit1 null mice are highly proliferative (Whitehead et al, 2004). As -catenin transcriptional activity is implicated in the expression of VEGF (Skurk et al, 2005) and endothelial cell proliferation (Goodwin et al, 2006), we asked whether the expression of VEGFA (Vegfa) or cyclinD1 (Ccnd1) is…”

Section: Krit1 Deficiency Leads To Increased Intestinal Adenoma Formamentioning

confidence: 99%

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Glading

Ginsberg

2010

Disease Models &Amp; Mechanisms

105

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SUMMARYKRIT1, also called CCM1, is a member of a multiprotein complex that contains the products of the CCM2 and PDCD10 (also known as CCM3) loci. Heterozygous loss of any of the genes that encode these proteins leads to cerebral cavernous malformations (CCM), which are vascular lesions that are found in around 0.5% of humans. KRIT1 mediates the stabilization of -catenin-containing endothelial cell-cell junctions downstream of the Rap1 GTPase. Here, we report that Rap1 and KRIT1 are negative regulators of canonical -catenin signaling in mice and that hemizygous Krit1 deficiency exacerbates -catenin-driven pathologies. Depletion of endothelial KRIT1 caused -catenin to dissociate from vascular endothelial (VE)-cadherin and to accumulate in the nucleus with consequent increases in -catenin-dependent transcription. Activation of Rap1 inhibited -catenindependent transcription in confluent endothelial cells; this effect required the presence of intact cell-cell junctions and KRIT1. These effects of KRIT1 were not limited to endothelial cells; the KRIT1 protein was expressed widely and its depletion increased -catenin signaling in epithelial cells. Moreover, a reduction in KRIT1 expression also increased -catenin signaling in vivo. Hemizygous deficiency of Krit1 resulted in a ~1.5-fold increase in intestinal polyps in the Apc Min/+ mouse, which was associated with increased -catenin-driven transcription. Thus, KRIT1 regulates -catenin signaling,and Krit1 +/-mice are more susceptible to -catenin-driven intestinal adenomas.

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“…Akt targets include Bad, 27 Forkhead (FKHR) factors, 28,29 IKKα, 30 Mdm2 (in p53-mediated apoptosis), 31 Yes-associated protein (YAP; in p73-mediated apoptosis), 32 caspase9, 33 and GSK3. 34,35 In addition to its role in cell survival, GSK-3 appears to regulate the cell cycle, 36 the trafficking and recycling of α v β 3 and α 5 β 1 integrins 37 and cell proliferation. 3 It is important to take into consideration that Akt is also capable of controlling long-term cellular responses by regulating gene expression at the level of transcription and translation.…”

Section: Akt Signaling In Endothelial Cellsmentioning

confidence: 99%