Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: Co-operation with Src tyrosine kinase

Obasanjo-Blackshire, Kofo; Mesquita, Rui F. D. S.; Jabr, Rita I.; Molkentin, Jeffery D.; Hart, Stephen L.; Marber, Michael; Xia, Yang; Heads, Richard J.

doi:10.1016/j.cardiores.2006.05.026

Cited by 44 publications

(36 citation statements)

References 35 publications

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“…The regulation of the iNOS gene promoter by calcineurin has been reported (36). LPS-induced iNOS expression in the heart was abrogated by the pharmacological inhibition of calcineurin (36).…”

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confidence: 99%

“…heart block; sodium current; sudden death; inducible nitric oxide synthase; transgenic overexpression of calcineurin TRANSGENIC OVEREXPRESSION of constitutively active calcineurin (CN/Tg) in cardiac myocytes results in profound concentric hypertrophy followed by ventricular dilatation, interstitial fibrosis, heart failure, and eventually sudden cardiac death (13,26,32,33,40). The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6, 10, 27, 36).Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36).…”

mentioning

confidence: 99%

“…Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36).…”

mentioning

confidence: 99%

“…The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6,10,27,36).…”

mentioning

confidence: 99%

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iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

Somers

Beck²,

Lees‐Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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HJ. iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin. Am J Physiol Heart Circ Physiol 295: H1122-H1131, 2008. First published July 11, 2008 doi:10.1152/ajpheart.00386.2008.-Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS Ϫ/Ϫ and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS Ϫ/Ϫ mice had improved systolic performance (P Ͻ 0.001) and less heart block (P Ͻ 0.0001); larger sodium current density and lower serum TNF-␣ levels (P Ͻ 0.03); and less apoptosis (P Ͻ 0.01) resulting in improved survival (P Ͻ 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS Ϫ/Ϫ mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BMderived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin. heart block; sodium current; sudden death; inducible nitric oxide synthase; transgenic overexpression of calcineurin TRANSGENIC OVEREXPRESSION of constitutively active calcineurin (CN/Tg) in cardiac myocytes results in profound concentric hypertrophy followed by ventricular dilatation, interstitial fibrosis, heart failure, and eventually sudden cardiac death (13,26,32,33,40). The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6, 10, 27, 36).Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36). LPS-induced iNOS expression in the heart was abrogated by the pharmacological inhibition of calcineurin (36). Similarly, LPS induced the expression of iNOS in wild-type (WT) hearts but not in the calcineurin A␤ knockout hearts (36). Reciprocally, the overexpression of constitutively active calcineurin in isolated cardiomyocytes caused the dephosphorylation and nuclear accumulation of the transcription factor family originally defined as nuclear factor of activated T-cells (NFAT)c1 and induced strong iNOS expression (36). In addition, chromatin immunoprecipitation confirmed the calcineurin-dependent binding of NFATc1 to the iNOS promoter (36). These data are co...

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

“…The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6,10,27,36).…”

mentioning

confidence: 99%

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iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

Somers

Beck²,

Lees‐Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is generally accepted that NF-κB predominantly regulates the expression level of iNOS proteins (30). However, it has also been reported that iNOS proteins are induced by the constitutive activation of calcineurin-NFAT signaling in cardiomyocytes (31). In accordance with this, the expression of a constitutively active mutant of NFAT (NFAT-CA) decreased AT 1 R-stimulated Ca 2+ response, which was completely abolished by the treatment with L-NAME or 1400W (Fig.…”

Section: P2ymentioning

confidence: 55%

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y ₂ receptor stimulation through S-nitrosylation of NF-κB

Nishida

Mariko

Reiko

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Cross-talk between G protein-coupled receptor (GPCR) signaling pathways serves to fine tune cellular responsiveness by neurohumoral factors. Accumulating evidence has implicated nitric oxide (NO)-based signaling downstream of GPCRs, but the molecular details are unknown. Here, we show that adenosine triphosphate (ATP) decreases angiotensin type 1 receptor (AT 1 R) density through NO-mediated S-nitrosylation of nuclear factor κB (NF-κB) in rat cardiac fibroblasts. Stimulation of purinergic P2Y 2 receptor by ATP increased expression of inducible NO synthase (iNOS) through activation of nuclear factor of activated T cells, NFATc1 and NFATc3. The ATP-induced iNOS interacted with p65 subunit of NF-κB in the cytosol through flavin-binding domain, which was indispensable for the locally generated NO-mediated S-nitrosylation of p65 at Cys38. β-Arrestins anchored the formation of p65/ IκBα/β-arrestins/iNOS quaternary complex. The S-nitrosylated p65 resulted in decreases in NF-κB transcriptional activity and AT 1 R density. In pressure-overloaded mouse hearts, ATP released from cardiomyocytes led to decrease in AT 1 R density through iNOS-mediated S-nitrosylation of p65. These results show a unique regulatory mechanism of heterologous regulation of GPCRs in which cysteine modification of transcriptional factor rather than protein phosphorylation plays essential roles.angiotensin receptor | Ca 2+ signaling | calcineurin | signaling complex | posttranslational modification G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors, which play a critical role in regulating multiple physiological functions (1, 2). Abnormal activation or up-regulation of GPCRs is a major cause of various diseases (3), and about 40% of drugs that are widely used for therapeutic treatment all over the world may directly or indirectly target GPCRs.An important adaptive response of the cell against multiple extracellular stimuli is receptor desensitization, which refers to the reduction of receptor responsiveness despite continuing agonist stimulation. GPCRs have developed elaborate means of turning off signal (4). One mechanism for desensitization is receptor down-regulation, which refers to the net loss of receptors from the cell by a decrease in receptor synthesis, a destabilization of receptor mRNA, or an increase in receptor degradation (4, 5).Two major patterns of down-regulation have been characterized; homologous (or agonist specific) down-regulation and heterologous (or agonist nonspecific) down-regulation (6). The homologous down-regulation indicates that stimulation of one GPCR over time by the agonist reduces expression levels of the same GPCR, without substantial effect on other GPCRs present in the same cell. In contrast, heterologous down-regulation indicates that stimulation of one GPCR reduces expression levels of different GPCR. Although the molecular mechanism of homologous down-regulation has been well analyzed using β-adrenergic receptors (βARs) (4, 5), the mechanism(s) underlying heterologous down-re...

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The Use of Protein Markers for the Estimation of the Postmortem Interval

Poloz

O’Day

2011

Forensic Pathology Reviews

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Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: Co-operation with Src tyrosine kinase

Abstract: These results support a cardioprotective role for calcineurin mediated by NFAT-dependent induction of iNOS expression and co-operativity between calcineurin and Src.

Cited by 44 publications

References 35 publications

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y ₂ receptor stimulation through S-nitrosylation of NF-κB

The Use of Protein Markers for the Estimation of the Postmortem Interval

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Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: Co-operation with Src tyrosine kinase

Abstract: These results support a cardioprotective role for calcineurin mediated by NFAT-dependent induction of iNOS expression and co-operativity between calcineurin and Src.

Cited by 44 publications

References 35 publications

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y 2 receptor stimulation through S-nitrosylation of NF-κB

The Use of Protein Markers for the Estimation of the Postmortem Interval

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Product

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Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y ₂ receptor stimulation through S-nitrosylation of NF-κB