Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17β-estradiol in the Male Rat Heart

Filice, E.; Angelone, Tommaso; Francesco, Ernestina Marianna De; Pellegrino, Daniela; Maggiolini, Marcello; Cerra, Maria Carmela

doi:10.1159/000331712

Cited by 22 publications

(16 citation statements)

References 56 publications

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“…Recently, Chen and coworkers (14) showed that endogenous H 2 S contributes to inactivate SERCA2a pump, and thus SR Ca 2ϩ uptake through PLN dephosphorylation. Our previous studies have demonstrated an important role of PLN in the lusitropic action of several cardioactive substances, such as catestatin and 17-␤-estradiol through both phosphorylation and S-nytrosylation mechanism (5,6,19). Together with the literature data, we suggested PLN S-sulfhydration as an alternative mechanism for SERCA2a regulation, with putative consequences on the H 2 S-dependent negative inotropic and lusitropic actions.…”

Section: Protein S-sulfhydrationsupporting

confidence: 66%

Akt/eNOS signaling and PLN S-sulfhydration are involved in H₂S-dependent cardiac effects in frog and rat

Mazza

Pasqua

Cerra

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Hydrogen sulfide (H 2S) has recently emerged as an important mediator of mammalian cardiovascular homeostasis. In nonmammalian vertebrates, little is known about the cardiac effects of H 2S. This study aimed to evaluate, in the avascular heart of the frog, Rana esculenta, whether and to what extent H 2S affects the cardiac performance, and what is the mechanism of action responsible for the observed effects. Results were analyzed in relation to those obtained in the rat heart, used as the mammalian model. Isolated and perfused (working and Langendorff) hearts, Western blot analysis, and modified biotin switch (S-sulfhydration) assay were used. In the frog heart, NaHS (used as H 2S donor, 10 Ϫ12 /10 Ϫ7 M) dose-dependently decreased inotropism. This effect was reduced by glibenclamide (K ATP channels blocker), 3-a]quinoxalin-1-one (guanylyl cyclase inhibitor), KT 5823 (PKG inhibitor), and it was blocked by Akt1/2 (Akt inhibitor) and by detergent Triton X-100. In the rat, in addition to the classic negative inotropic effect, NaHS (10 Ϫ12 /10 Ϫ7 M) exhibited negative lusitropism. In both frog and rat hearts, NaHS treatment induced Akt and eNOS phosphorylation and an increased cardiac protein S-sulfhydration that, in the rat heart, includes phospholamban. Our data suggest that H 2S represents a phylogenetically conserved cardioactive molecule. Results obtained on the rat heart extend the role of H 2S also to cardiac relaxation. H2S effects involve K ATP channels, the Akt/NOS-cGMP/PKG pathway, and S-sulfhydration of cardiac proteins. hydrogen sulfide; inotropism; lusitropism; nitric oxide synthasecGMP/PKG pathway HYDROGEN SULFIDE (H 2 S), AN endogenous signaling molecule, influences a wide range of physiological and pathological processes. First described as a physiological mediator in the brain (1) and then in the cardiovascular system (24), H 2 S quickly emerged as a cytoprotective molecule with effects on neurotransmission, neuroprotection, insulin release, inflammation, vessel motility, and cardioprotection (51). Along with nitric oxide (NO) and carbon monoxide (CO), it is now recognized as the third endogenous gasotransmitter (20,48,49). In mammals, H 2 S is produced via the cysteine metabolic enzymes cystathionine ␤-synthase (CBS), cystathionine ␥-lyase (CSE) (1, 24), and the combined actions of cysteine aminotransferase and 3-mercaptopyruvate sulfurtransferase (42,43). CBS predominates in the brain, while CSE is the major H 2 S-producing enzyme in the cardiovascular system, where it is present in both vascular smooth muscle and endothelium (24, 52).In all vertebrates, H 2 S was suggested to act as an oxygen sensor, being possibly involved in vascular responses to changes in oxygen availability. During normoxia, cytosolic H 2 S biosynthesis is counteracted by mitochondrial H 2 S oxidation. In contrast, during hypoxia, the low oxygen levels allow vascular H 2 S accumulation, thus modulating the vascular tone (35, 38).The cardiovascular role of H 2 S is well documented in mammals. H 2 S-induced vasodilation of mam...

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Section: Protein S-sulfhydrationsupporting

confidence: 66%

Akt/eNOS signaling and PLN S-sulfhydration are involved in H₂S-dependent cardiac effects in frog and rat

Mazza

Pasqua

Cerra

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Thus, PLN levels and activity may also be under the control of myostatin or a myostatin-regulated factor, as with SERCA2a. Estradiol inhibits, rather than stimulates, PLN activation and does not appear to regulate PLN expression (74). Gonadal steroids may therefore influence myostatin sensitivity, but are likely not directly responsible for the noted sexual dimorphism.…”

Section: Discussionmentioning

confidence: 95%

Myostatin Regulates Tissue Potency and Cardiac Calcium-Handling Proteins

Jackson

Rodgers

2014

Endocrinology

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Attenuating myostatin enhances striated muscle growth, reduces adiposity, and improves cardiac contractility. To determine whether myostatin influences tissue potency in a manner that could control such pleiotropic actions, we generated label-retaining mice with wild-type and mstn(-/-) (Jekyll) backgrounds in which slow-cycling stem, transit-amplifying, and progenitor cells are preferentially labeled by histone 2B/green fluorescent protein. Jekyll mice were born with fewer label-retaining cells (LRCs) in muscle and heart, consistent with increased stem/progenitor cell contributions to embryonic growth of both tissues. Cardiac LRC recruitment from noncardiac sources occurred in both groups, but lasted longer in Jekyll hearts, whereas heightened β-adrenergic sensitivity of mstn(-/-) hearts was explained by elevated SERCA2a, phospholamban, and β2-adrenergic receptor levels. Jekyll mice were also born with more adipose LRCs despite significantly smaller tissue weights. Reduced adiposity in mstn(-/-) animals is therefore due to reduced lipid deposition as adipoprogenitor pools appear to be enhanced. By contrast, increased bone densities of mstn(-/-) mice are likely compensatory to hypermuscularity because LRC counts were similar in Jekyll and wild-type tibia. Myostatin therefore significantly influences the potency of different tissues, not just muscle, as well as cardiac Ca²⁺-handling proteins. Thus, the pleiotropic phenotype of mstn(-/-) animals may not be due to enhanced muscle development per se, but also to altered stem/progenitor cell pools that ultimately influence tissue potency.

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“…Phosphorylation of Akt at Thr308 and Ser473 was also prevented by the MEK inhibitor PD98059 (50 µM) [19] (Fig. 2D) and the ERK1/2 inhibitor FR180204 (10 µM) [20,21] (Fig.…”

Section: Resultsmentioning

confidence: 99%

Crosstalk between PI3 Kinase/PDK1/Akt/Rac1 and Ras/Raf/MEK/ERK Pathways Downstream PDGF Receptor

Niba

Nagaya

Kanno

et al. 2013

Cell Physiol Biochem

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Background/Aims: Our earlier studies suggested crosstalk between IRS/PI3 kinase/PDK1/Akt/Rac1/ROCK and (Shc2/Grb2/SOS)/Ras/Raf/MEK/ERK pathways downstream PDGF-ββ receptor responsible for chemotaxis and proliferation of malignant mesothelioma cells. The present study was conducted to obtain evidence for this. Methods: To assess activation of Akt, MEK, and ERK, Western blotting was carried out on MSTO-211H malignant mesothelioma cells using antibodies against phospho-Thr308-Akt, phopho-Ser473-Akt, Akt, phospho-MEK, MEK, phopho-ERK1/2, and ERK1/2. To knock-down Akt, PI3 kinase, PDK1, and Rac1, siRNAs silencing each-targeted gene were constructed and transfected into cells. To monitor Rac1 activity, FRET monitoring was carried out on living and fixed cells. Results: ERK was activated under the basal conditions in MSTO-211H cells, and the activation was prevented by inhibitors for PI3 kinase, PDK1, Akt, and Rac1 or by knocking-down PI3 kinase, PDK1, Akt, and Rac1. Akt was also activated under the basal conditions, and the activation was suppressed by a MEK inhibitor and an ERK1/2 inhibitor. In the FRET analysis, Rac1 was activated under the basal conditions, and the activation was inhibited by a MEK inhibitor and an ERK1/2 inhibitor. Conclusion: The results of the present study show that ERK could be activated by PI3 kinase, PDK1, Akt, and Rac1 and that alternatively, Akt and Rac1 could be activated by MEK and ERK in MSTO-211H cells.

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Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17β-estradiol in the Male Rat Heart

Cited by 22 publications

References 56 publications

Akt/eNOS signaling and PLN S-sulfhydration are involved in H₂S-dependent cardiac effects in frog and rat

Akt/eNOS signaling and PLN S-sulfhydration are involved in H₂S-dependent cardiac effects in frog and rat

Myostatin Regulates Tissue Potency and Cardiac Calcium-Handling Proteins

Crosstalk between PI3 Kinase/PDK1/Akt/Rac1 and Ras/Raf/MEK/ERK Pathways Downstream PDGF Receptor

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Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17β-estradiol in the Male Rat Heart

Cited by 22 publications

References 56 publications

Akt/eNOS signaling and PLN S-sulfhydration are involved in H2S-dependent cardiac effects in frog and rat

Akt/eNOS signaling and PLN S-sulfhydration are involved in H2S-dependent cardiac effects in frog and rat

Myostatin Regulates Tissue Potency and Cardiac Calcium-Handling Proteins

Crosstalk between PI3 Kinase/PDK1/Akt/Rac1 and Ras/Raf/MEK/ERK Pathways Downstream PDGF Receptor

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Akt/eNOS signaling and PLN S-sulfhydration are involved in H₂S-dependent cardiac effects in frog and rat

Akt/eNOS signaling and PLN S-sulfhydration are involved in H₂S-dependent cardiac effects in frog and rat