Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

doi:10.1016/j.bbrc.2008.03.100

Cited by 86 publications

(69 citation statements)

References 22 publications

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“…Furthermore, they show that the inhibition of Akt abrogated CTGF-induced hypertrophy, indicating that CTGF is a novel hypertrophic factor in cardiac myocytes. 33 In addition, antihypertensive treatment had a mitigating effect on the changes in gene expression in this group. As expected, CTGF expression, which is known to be angiotensin-II driven, was downregulated to a similar degree by both the QHI and LOS treatment groups, despite the blood pressure difference between these two groups.…”

Section: Proliferation/cell Growthmentioning

confidence: 83%

“…30 An increase in connective tissue growth factor (CTGF) expression was seen in late LVH, similar to findings in other models of cardiac hypertrophy, 31 and its well-characterized profibrotic effect, including its ability to induce cardiac fibroblast proliferation and also extracellular matrix expansion. 32 Hayata et al 33 have shown that cardiac myocytes stimulated with CTGF and its C-terminalregion peptide showed an increase in the cell surface area. Furthermore, they show that the inhibition of Akt abrogated CTGF-induced hypertrophy, indicating that CTGF is a novel hypertrophic factor in cardiac myocytes.…”

Section: Proliferation/cell Growthmentioning

confidence: 99%

“…Signaling pathways evoked in LVH included the serine/threonine kinase Akt (1 and 2), the role of which in LVH has been well documented. 26,33 Two G-protein-coupled receptors were also present in this cluster, including the a 1D -adrenergic receptor and the G-protein-signaling modulator 1 (also known as AGS3). These aligned with the ubiquitously expressed guanine nucleotide-binding protein, a-12 (G a 12), which can couple with a wide range of receptors, including angiotensin-II and endothelin.…”

Section: Signal Transductionmentioning

confidence: 99%

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Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

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Section: Proliferation/cell Growthmentioning

confidence: 83%

Section: Proliferation/cell Growthmentioning

confidence: 99%

Section: Signal Transductionmentioning

confidence: 99%

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Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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“…In human atrial fibrillation, CCN2 is upregulated and influences the expression of connexin 43 or N-cadherin in the atrial cells [13]. It has been previously postulated that CCN2 promotes fibroblast proliferation and hypertrophy of cardiac myocytes in vitro and in vivo [14,15]. In the rat model of myocardial infarction, CCN2 was shown to be involved in fibrosis and its expression increased in the viable myocardium of the left ventricle late after the index event [16].…”

Section: Discussionmentioning

confidence: 99%

Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure

Bonda

Kamiński

Dziemidowicz

et al. 2012

Folia Histochem Cytobiol.

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Previous studies have reported the upregulation of CCN proteins early after acute heart injury. The aim of the present work was to evaluate the expression of the CCN1 and CCN2 proteins and their regulation by angiotensin II in the atrial myocardium of a chronically failing heart. Male adult mice were subjected to ligation of the left coronary artery to produce myocardial infarction (the MI group), and 16 of them were treated for 12 weeks with the AT1 receptor antagonist telmisartan (the MI-Tel group). Sham-operated mice served as controls. The expression of proteins was evaluated by immunohistochemistry 12 weeks after the operation. In shamoperated mice, stainings for CCN1 and CCN2 proteins were positive within atrial cardiomyocytes. CCN1-positive reaction revealed diffused cytoplasmic localization, while CCN2 was present mainly within the perinuclear cytoplasm. CCN1 was upregulated in the MI group, while CCN2 remained at basal level. Telmisartan prevented the upregulation of CCN1 and decreased CCN2 level. We compared the experimental data with the expression of CCN1 and CCN2 proteins in human right atrial appendages. We found an inverse, but not significant, relation between the level of either protein and the left ventricular ejection fraction. This suggests a similar atrial regulation of CCN1 and CCN2 expression also in humans. We conclude that in the murine atria, CCN1 and CCN2 proteins are expressed constitutively. In chronic heart failure, CCN proteins tend to be upregulated, which may be related to the action of angiotensin II.

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“…Multiple genes implicated in tissue remodeling (Holmbeck et al 1999, Ichimura et al 2004, Koh et al 2005 were identified and tabulated separately (Table 4), including plasminogen activator inhibitor-1 (Serpine1), matrix metalloproteinase-14 (Mmp14), connective tissue growth factor (Ctgf ), kidney injury molecule-1 (Kim1), mast cell protease-4 (Mcpt4), and heat shock protein 70 (Hspa1a). Several of these genes are proposed to play important roles in muscle homeostasis, for example the IGF1-binding protein, CTGF, is involved in muscle, bone, and liver cell regeneration, and inhibits the transforming growth factor (TGF)/bone morphogenetic protein (BMP) pathway that limits muscle growth (Ohnishi et al 1998, Pummila et al 2007, Hayata et al 2008, Smerdel-Ramoya et al 2008. In terms of inflammation, chemokine C-C ligand-7, Ccl7 and chemokine C-C ligand-2, Ccl2 were up-regulated by microarray and confirmed by qRT-PCR (Fig.…”

Section: Microarray Screen For Androgen-responsive Genes In the Soleusmentioning

confidence: 99%

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Gentile¹,

Nantermet²,

Vogel³

et al. 2009

Journal of Molecular Endocrinology

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Androgens promote anabolism in the musculoskeletal system while generally repressing adiposity, leading to lean body composition. Circulating androgens decline with age, contributing to frailty, osteoporosis, and obesity; however, the mechanisms by which androgens modulate body composition are largely unknown. Here, we demonstrate that aged castrated rats develop increased fat mass, reduced muscle mass and strength, and lower bone mass. Treatment with testosterone or 5a-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable testosterone increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of IGF1 and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, monocyte nuclear factor, or myostatin. A genome-wide microarray screen was also performed to identify potential pro-myogenic genes that respond to androgen receptor activation in vivo within 24 h. Of 24 000 genes examined, 70 candidate genes were identified whose functions suggest initiation of remodeling and regeneration, including the type II muscle genes for myosin heavy chain type II and parvalbumin and the chemokine monocyte chemoattractant protein-1. Interestingly, Axin and Axin2, negative regulators of b-catenin, were repressed, indicating modulation of the b-catenin pathway. DHT increased total levels of b-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear b-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of b-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.

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Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

Cited by 86 publications

References 22 publications

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

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