Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin

Zou, Yunzeng; Yao, Atsushi; Zhu, Weidong; Kudoh, Sumiyo; Hiroi, Yukio; Shimoyama, Masaki; Uozumi, Hiroki; Kohmoto, Osami; Takahashi, Toshiyuki; Shibasaki, Futoshi; Nagai, Ryozo; Yazaki, Yoshio; Komuro, Issei

doi:10.1161/hc2601.090987

Cited by 116 publications

(80 citation statements)

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“…5,6 More recently, activation of 44-to 42-kDa extracellular signalregulated protein kinases through a calcineurin-dependent mechanism was shown to participate in the development of Iso-induced CH. 7 Our results show that prevention of CH development by the NHE-1 inhibitor in Iso-treated rats was accompanied by normalization of NHE-1 expression and myocardial pH i . The observation that NHE-1 inhibitors exert antihypertrophic effect is not new.…”

Section: Discussionsupporting

confidence: 50%

“…Although several mechanisms have been imputed to underlie the cardiotrophic action of Iso, [5][6][7] the exact nature is still under debate. Because cumulative evidence supports a cause-effect link between the activity of the Na ϩ /H ϩ exchanger (NHE) and cardiac cell growth (Cingolani and Camilión de Hurtado 8 ), we sought to analyze the possible role of NHE activity in Iso-induced CH by taking advantage of the specific, orally active inhibitor against NHE isoform 1 (NHE-1).…”

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confidence: 99%

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Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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Abstract-Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either ␣-or ␤-adrenergic stimulation. Because an association between the Na ϩ /H ϩ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na ϩ /H ϩ exchanger activity (3 mg · kg) was given to male Wistar rats for 30 days. Sex-and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenolϩBIIB723-treated group. Heart weight-to-body weight ratio at necropsy was 2.44Ϯ0.11 in controls and increased to 3.35Ϯ0.10 (PϽ0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82Ϯ0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na ϩ /H ϩ exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45Ϯ0.11 vs 0.91Ϯ0.05 arbitrary units, PϽ0.05). This effect was significantly reduced by BIIB723 (1.17Ϯ0.02, PϽ0.05). In conclusion, our results show that Na ϩ /H ϩ exchanger inhibition prevented the development of isoproterenolinduced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy. Key Words: hypertrophy, cardiac Ⅲ signal transduction Ⅲ antiporters Ⅲ fibrosis Ⅲ adrenergic receptor agonists I ncreased sympathetic activity is often implicated in the development of cardiac hypertrophy (CH). A correlation between cardiac mass and sympathetic activity was found in young hypertensive humans, 1 and long-term infusion of subpressor doses of norepinephrine leads to CH in dogs and rats. 2,3 This cardiotrophic effect of catecholamines involves both ␣-or ␤-adrenergic receptors. 4 It is well recognized that repeated or continuous injections of the ␤-adrenoceptor agonist isoproterenol (Iso) causes, within days, clear CH, 5 and therefore it represents a useful experimental model.Although several mechanisms have been imputed to underlie the cardiotrophic action of Iso, 5-7 the exact nature is still under debate. Because cumulative evidence supports a cause-effect link between the activity of the Na ϩ /H ϩ exchanger (NHE) and cardiac cell growth (Cingolani and Camilión de Hurtado 8 ), we sought to analyze the possible role of NHE activity in Iso-induced CH by taking advantage of the specific, orally active inhibitor against NHE isoform 1 (NHE-1). This study provides evidence indicating a key role for NHE-1 activity as a mechanism underlying the development of CH and fibrosis induced by I...

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Section: Discussionsupporting

confidence: 50%

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confidence: 99%

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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“…These findings are in marked contrast to the responses of other previously examined cell types. Upon ␤ 2 -AR activation in cardiomyocytes (26,30), HEK293 cells (29,32), COS-7 cells (28,31), and Chinese hamster ovary cells (27), ␤ 2 -AR activation results in increased ERK phosphorylation. Here we elucidate the mechanism by which ␤ 2 -AR activation decreases ERK phosphorylation and migration.…”

Section: Discussionmentioning

confidence: 99%

PP2A Activation by β2-Adrenergic Receptor Agonists

Pullar

Chen

Isseroff

2003

Journal of Biological Chemistry

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Understanding the mechanisms that regulate cell migration is important for devising novel therapies to control metastasis or enhance wound healing. Previously, we demonstrated that ␤ 2 -adrenergic receptor (␤ 2 -AR) activation in keratinocytes inhibited their migration by decreasing the phosphorylation of a critical promigratory signaling component, the extracellular signal-related kinase (ERK). Here we demonstrate that ␤ 2 -ARinduced inhibition of migration is mediated by the activation of the serine/threonine phosphatase PP2A. Pretreating human keratinocytes with the PP2A inhibitor, okadaic acid, prevented the ␤ 2 -AR-induced inhibition of migration, either as isolated cells or as a confluent sheet of cells repairing an in vitro "wound" and also prevented the ␤ 2 -AR-induced reduction in ERK phosphorylation. Similar results were obtained with human corneal epithelial cells. In keratinocytes, immunoprecipitation studies revealed that ␤ 2 -AR activation resulted in the rapid association of ␤ 2 -AR with PP2A as well as a 37% increase in association of PP2A with ERK2. Finally, ␤ 2 -AR activation resulted in a rapid and transient 2-fold increase in PP2A activity. Thus, we provide the first evidence that ␤ 2 -AR activation in keratinocytes modulates migration via a novel pathway utilizing PP2A to alter the promigratory signaling cascade. Exploiting this pathway may result in novel therapeutic approaches for control of epithelial cell migration.When skin is wounded, keratinocytes within the epidermis must migrate from the wound edges to re-epithelialize the wound surface (1). One of the best characterized mediators of keratinocyte migration is the epidermal growth factor receptor (EGFR) 1 (2-4). The mitogen-activated protein (MAP) kinases, extracellular signal-related kinase 1 (ERK1) and ERK2, are activated upon EGF binding to its cognate receptor (reviewed in Ref. 5). They are activated by phosphorylation on both conserved threonine and tyrosine residues and inactivated upon dephosphorylation by dual specificity phosphatases, tyrosine phosphatases, and serine/threonine-specific phosphatases (5-9). The activation of ERK is tightly controlled. The MAP kinase pathway is usually only transiently activated, and its constitutive activation is sufficient to cause the oncogenic transformation of some cell types (10). Inhibiting ERK phosphorylation and activation prevents growth factor-induced keratinocyte migration (11), demonstrating the pivotal role of ERK in the keratinocyte promigratory signaling pathways (11-13).In addition to the EGFR, keratinocytes also express high levels of the G-protein-coupled receptor, the ␤ 2 -adrenergic receptor, (␤ 2 -AR) (14, 15), whose functional role in the epidermis has not yet been elucidated. Keratinocytes do not express the ␤ 1 -AR (16). Earlier studies have investigated the role of ␤-ARs in epithelial wound healing and migration, but the results have been paradoxical. ␤-Antagonists have been reported to either delay (17, 18) or enhance (19) corneal epithelial wound healing, and ␤-agon...

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“…Selective β1-AR stimulation caused hypertrophy growth of ventricular cardiomyocytes by a mechanism that is independent of cAMP but dependent on a tyrosine kinase and CaMKII (38,43). The MAPK pathway has been implicated in cardiac hypertrophy induced by β2-AR stimulation (44,45). PI3Kγ, which is activated through Gi-associated Gβγ, plays an essential role in isoproterenol-induced cardiac hypertrophy and heart failure (46,47).…”

Section: Pka-dependent Phosphorylation and Nuclear Retention Of Hdac5mentioning

confidence: 99%

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

Kim

Zhao

et al. 2010

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

118

116

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Dynamic nucleocytoplasmic shuttling of class IIa histone deacetylases (HDACs) is a fundamental mechanism regulating gene transcription. Recent studies have identified several protein kinases that phosphorylate HDAC5, leading to its exportation from the nucleus. However, the negative regulatory mechanisms for HDAC5 nuclear exclusion remain largely unknown. Here we show that cAMPactivated protein kinase A (PKA) specifically phosphorylates HDAC5 and prevents its export from the nucleus, leading to suppression of gene transcription. PKA interacts directly with HDAC5 and phosphorylates HDAC5 at serine 280, an evolutionarily conserved site. Phosphorylation of HDAC5 by PKA interrupts the association of HDAC5 with protein chaperone 14-3-3 and hence inhibits stress signal-induced nuclear export of HDAC5. An HDAC5 mutant that mimics PKA-dependent phosphorylation localizes in the nucleus and acts as a dominant inhibitor for myocyte enhancer factor 2 transcriptional activity. Molecular manipulations of HDAC5 show that PKA-phosphorylated HDAC5 inhibits cardiac fetal gene expression and cardiomyocyte hypertrophy. Our findings identify HDAC5 as a substrate of PKA and reveal a cAMP/PKA-dependent pathway that controls HDAC5 nucleocytoplasmic shuttling and represses gene transcription. This pathway may represent a mechanism by which cAMP/PKA signaling modulates a wide range of biological functions and human diseases such as cardiomyopathy.nucleocytoplasmic shuttling | phosphorylation G ene transcription is governed in part by the acetylation and deacetylation of histones, the latter of which is mediated by histone deacetylases (HDACs) (1-4). In particular, class IIa HDACs, such as HDAC5, acting as transcriptional repressors, have been implicated in cardiac hypertrophy, skeletal muscle differentiation, and angiogenesis (5-10). Dynamic nucleocytoplasmic shuttling has been proposed as a fundamental mechanism regulating the function of class IIa HDACs (1, 11-13). Recent studies have identified several protein kinases, including calmodulin-dependent protein kinases (CaMKs), protein kinase D (PKD) and salt-inducible kinase, that phosphorylate HDAC5, leading to its export from the nucleus (1, 9, 14). However, much less is understood about the negative regulatory mechanisms for the nuclear exclusion of HDAC5 (15). To date, specific protein kinases that may inhibit export of HDAC5 from the nucleus have not been identified.The cAMP/protein kinase A (PKA) signaling pathway regulates a variety of cellular functions and numerous important biological processes (16,17). Many of the effects of cAMP/PKA are mediated via changes in gene transcription. A large body of research has defined the cAMP-response element binding (CREB) proteins as PKA substrates that mediate an increase in gene expression in response to cAMP (18)(19)(20). However, whether and how the cAMP/PKA pathway inhibits gene expression remains unclear. In this study, we found that cAMP/PKA signaling represses gene transcription and cardiomyocyte hypertrophy by phosphorylating HDAC5 ...

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Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin

Cited by 116 publications

References 43 publications

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

PP2A Activation by β2-Adrenergic Receptor Agonists

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

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Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin

Cited by 116 publications

References 43 publications

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

PP2A Activation by β2-Adrenergic Receptor Agonists

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

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Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition