Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3β/mTOR signaling pathway

Diniz, Gabriela Placoná; Carneiro‐Ramos, Marcela Sorelli; Barreto‐Chaves, Maria Luíza Morais

doi:10.1007/s00395-009-0043-1

Cited by 94 publications

(107 citation statements)

References 59 publications

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“…Samples were run in duplicate, and the real-time RT-PCR data were normalized to b-actin, as we have previously certified that variations in TH levels do not alter b-actin mRNA levels (Diniz et al 2009, Carneiro-Ramos et al 2010.…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

“…04% SDS, 20 mmol/l aprotinin, 20 mmol/l pepstatin, 20 mmol/l leupepstatin, 40 mmol/l phenylmethylsulfonyl fluoride, and 100 mmol/l orthovanadate), and immunoblotting was performed as described previously (Diniz et al 2009). Protein concentrations were analyzed by the Bradford method.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…We have recently demonstrated that T 3 induces a rapid increase in AT1R mRNA and protein levels in isolated cardiomyocytes (Diniz et al 2009). In order to investigate the possible mechanisms implicated in these rapid events, the cardiomyocytes were treated with T 3 (10 nmol/l) for 5, 10, 15, and 30 min.…”

Section: T 3 Rapidly Raises the At1r Levels In Cardiomyocytesmentioning

confidence: 99%

“…A growing body of evidence indicates that the renin-angiotensin system (RAS) has a critical role in the development of cardiac hypertrophy found in hyperthyroidism and the local RAS, present in the cardiomyocytes, is directly implicated in this process (Diniz et al 2009, Carneiro-Ramos et al 2010. In this sense, the contribution of the RAS in this pathological condition has been demonstrated by several studies reported in the literature, which showed that AT1R receptor blockade and angiotensin-converting enzyme inhibition attenuate or prevent the development of cardiac hypertrophy induced by THs (Kobori et al 1997, Asahi et al 2001, Basset et al 2001, Hu et al 2003, Pantos et al 2005.…”

Section: Introductionmentioning

confidence: 99%

“…We have recently demonstrated that the angiotensin II type 1 receptor (AT1R) is a critical mediator of the ability of triiodothyronine (T 3 ) to induce cardiomyocyte hypertrophy as well as the rapid effect that T 3 has on the activation of the Akt/GSK-3b/mTOR signaling pathway (Diniz et al 2009). However, the molecular mechanisms underlying these rapid T 3 -promoted events are not yet known.…”

Section: Introductionmentioning

confidence: 99%

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New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

Diniz

Takano²,

Bruneto³

et al. 2012

Journal of Molecular Endocrinology

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The angiotensin II type 1 receptor (AT1R) is involved in the development of cardiac hypertrophy promoted by thyroid hormone. Recently, we demonstrated that triiodothyronine (T 3 ) rapidly increases AT1R mRNA and protein levels in cardiomyocyte cultures. However, the molecular mechanisms responsible for these rapid events are not yet known. In this study, we investigated the T 3 effect on AT1R mRNA polyadenylation in cultured cardiomyocytes as well as on the expression of microRNA-350 (miR-350), which targets AT1R mRNA. The transcriptional and translational actions mediated by T 3 on AT1R levels were also assessed. The total content of ubiquitinated proteins in cardiomyocytes treated with T 3 was investigated. Our data confirmed that T 3 rapidly raised AT1R mRNA and protein levels, as assessed by realtime PCR and western blotting respectively. The use of inhibitors of mRNA and protein synthesis prevented the rapid increase in AT1R protein levels mediated by T 3 . In addition, T 3 rapidly increased the poly-A tail length of the AT1R mRNA, as determined by rapid amplification of cDNA ends poly-A test, and decreased the content of ubiquitinated proteins in cardiomyocytes. On the other hand, T 3 treatment increased miR-350 expression. In parallel with its transcriptional and translational effects on the AT1R, T 3 exerted a rapid posttranscriptional action on AT1R mRNA polyadenylation, which might be contributing to increase transcript stability, as well as on translational efficiency, resulting to the rapid increase in AT1R mRNA expression and protein levels. Finally, these results show, for the first time, that T 3 rapidly triggers distinct mechanisms, which might contribute to the regulation of AT1R levels in cardiomyocytes.

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Section: Real-time Rt-pcrmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Section: T 3 Rapidly Raises the At1r Levels In Cardiomyocytesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

Diniz

Takano²,

Bruneto³

et al. 2012

Journal of Molecular Endocrinology

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Redox status and pro‐survival/pro‐apoptotic protein expression in the early cardiac hypertrophy induced by experimental hyperthyroidism

Fernandes

Dreher

Schenkel

et al. 2011

Cell Biochemistry & Function

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This study was conducted to analyse the redox status and redox-sensitive proteins that may contribute to a non-genomic mechanism of cardiac hypertrophy induction by hyperthyroidism. Wistar rats, treated with L-thyroxine (T4) during 2 weeks (12 mg·l(-1) in drinking water), presented cardiac hypertrophy (68% higher than control), without signals of liver or lung congestion. Myocardial reduction of the reduced glutathione: oxidized glutathione (GSSG) ratio (45%) (redox status) and elevation in hydrogen peroxide concentration (H(2) O(2) ) (28%) were observed in hyperthyroid as compared with the control. No significant difference was found in thioredoxin (Trx), Trx reductase activity and Nrf2 (a transcriptional factor) protein expression between groups. Redox-sensitive proteins, quantified using Western blot, presented the following results: increased p-ERK: total extracellular-regulated kinase (ERK) (200%) and Bax:Bcl-2 (62%) ratios and reduced total-Akt (63%) and p-Akt (53%) expressions in the hyperthyroid rats as compared with the control. The redox imbalance, associated with increased immunocontent of a protein related to maladaptative growth (ERK) and reduced immunocontent of protein related to cytoprotection/survival (Akt), may suggest that the molecular scenario could favour the decompensation process of cardiac hypertrophy induced by experimental hyperthyroidism.

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Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3‐iodothyronamine on the cardiovascular system

Axelband

Dias

Ferrão

et al. 2010

Journal Cellular Physiology

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Thyroid hormones play a wide range of important physiological activities in almost all organism. As changes in these hormones levels-observed in hypothyroidism and hyperthyroidism-promote serious derangements of the cardiovascular system, it is important to know their mechanisms of action. Although the classic genomic actions which are dependent on interaction with nuclear receptors to modulate cardiac myocytes genes expression, there is growing evidence about T(3) and T(4)-triggered nongenomic pathways, resulted from their binding to plasma membrane, cytoplasm, or mitocondrial receptors that leads to a rapidly regulation of cardiac functions. Interestingly both actions converge to amplify thyroid hormone effects on cardiovascular system. T(3) and T(4) nongenomic actions modify inotropic and chronotropic effects, cardiac action potential duration, cardiac growth, and myocyte shape by protein translation through protein kinases-dependent signaling cascades, which include PKA, PKC, PI3K, and MAPK, and changes on ion channels and pumps activity. In respect to the decreased systemic vascular resistance seen in hyperthyroidism, T(3) appears to activate NOS or ATP-sensitive K(+) channels. In addition, a novel biologically active T(4)-derived metabolite has been described, 3-iodothyronamine, T(1)AM, which also acts through membrane receptors to mediate nongenomic cardiac effects. This metabolite influences the physiological manifestations of thyroid hormone actions by inducing opposite effects from those stimulated by T(3) and T(4), such as negative inotropic and chronotropic effects. Therefore, beyond genomic and nongenomic effects of thyroid hormones, it is crucial for there to be an equilibrium between T(3) or T(4) and T(1)AM levels for maintaining cardiac homeostasis.

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Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3β/mTOR signaling pathway

Cited by 94 publications

References 59 publications

New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

Redox status and pro‐survival/pro‐apoptotic protein expression in the early cardiac hypertrophy induced by experimental hyperthyroidism

Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3‐iodothyronamine on the cardiovascular system

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