Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through b-adrenoceptors

ABSTRACT: Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important to maintain cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for alfa1-adrenoceptor (alfa1AR)-stimulated cation entry and their upregulation is reportedly associated with pathological cardiac remodeling, but whether TRPC channels participate in physiological pump functions remains unclear. Here, we demonstrate that TRPC6-specific Zn2+ influx potentiates alfa-adrenoceptor (alfaAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of the trpc6 gene impairs sympathetic nerve-activated positive inotropy, but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts alfa1AR-stimulatedalfaAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting alfa-arrestin-mediated alfaAR internalization. Replacing two TRPC6-specific amino acids in the pore region with those of TRPC3 diminishes the alfa1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents the progression of heart failure in dilated cardiomyopathy mice. Our data provide evidence that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE189494 | GEO | 2022/09/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through b-adrenoceptors

Project description:Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through b-adrenoceptors

| PRJNA783279 | ENA

Pdx-1 activates islet M-NM-1- and M-NM-2-cell proliferation via a TRPC3/6- and ERK 1/2-regulated mechanism

Project description:The homeodomain transcription factor, Pdx-1, has important roles in pancreatic development and M-NM-2-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, co-overexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly M-NM-2-cell proliferation, whereas Pdx-1 stimulates both M-NM-1- and M-NM-2-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1- but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 and not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and siRNA-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates ERK1/2 phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1-stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1. We identified genes that were upregulated or downregulated at 48 h with Pdx-1 overexpression as compared to untreated and M-NM-2gal controls. We set up a microarray using primary rat islets that were left untreated or transduced with adenoviruses overexpressing M-NM-2gal or Pdx-1 for 48 h.

2013-09-01 | E-GEOD-49786 | biostudies-arrayexpress

Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase 2A signaling in cardiac myocytes by nitroxyl

Project description:Sympathetic activation is the main driver of cardiac inotropy and lusitropy. Stimulation of the -adrenoceptor (AR) signaling cascade leads to activation of cAMP-dependent protein kinase (PKA) and subsequent cardiac protein phosphorylation, which is counteracted by the corresponding protein phosphatases 2A (PP2A). Both, kinase and phosphatase are sensitive to oxidation. For PKA, the oxidant-mediated mode of regulation has been described to occur by interdisulfide formation between type I regulatory subunits (PKA-RI). Furthermore, oxidant-mediated intradisulfide formation in the catalytic subunit of PKA and PP2A was shown to inhibit kinase or phosphatase activity, respectively. Nitroxyl donors exert positive inotropic and lusitropic effects in cardiac myocytes.

2020-10-29 | PXD019808 | Pride

Pdx-1 activates islet α- and β-cell proliferation via a TRPC3/6- and ERK 1/2-regulated mechanism

Project description:The homeodomain transcription factor, Pdx-1, has important roles in pancreatic development and β-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, co-overexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly β-cell proliferation, whereas Pdx-1 stimulates both α- and β-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1- but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 and not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and siRNA-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates ERK1/2 phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1-stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1. We identified genes that were upregulated or downregulated at 48 h with Pdx-1 overexpression as compared to untreated and βgal controls.

2013-09-01 | GSE49786 | GEO

Atorvastatin Reduces Î²-Adrenergic Dysfunction in Rats with Diabetic Cardiomyopathy

Project description:Background: In the diabetic heart the Î²-adrenergic response is altered partly by down-regulation of the Î²1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the Î²3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to âpleiotropicâ effects. The objective of our study was to investigate the role of statin treatment on Î²-adrenergic dysfunction in diabetic rat cardiomyocytes. Methods: Î²-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline Â± SD. Results: Atorvastatin restored the impaired positive inotropic effect of Î²-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the Î²-adrenergic pathway and corrected the protein expression of Î²1-adrenoceptor and Î²1/Î²3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the Î²-adrenoceptor response. Conclusions: Atorvastatin restored the positive inotropic effect of the Î²-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the Î²-adrenergic signaling pathway, particularly through the NOS pathway.

2017-06-27 | E-MTAB-5594 | biostudies-arrayexpress

H3K4me3-marked histone orchestrates neutrophil plasticity from immunity to tissue regeneration

Project description:In this study, we used chromatin immunoprecipitation sequencing (ChIP-Seq) analysis of histone H3K4me3-marked, to identify various TSSs associated with LPS-, TNF-alfa- and IL-10-stimulated neutrophils from healthy individuals, as well as neutrophils derived from the patients with sepsis (systemic septic inflammation with LPS-stimulated neutrophils), NMOSD (aseptic inflammation with neutrophils pre-activated by TNF-alfa and periodontitis (localized self-limiting septic inflammation with IL-10-positive neutrophils). We provided comprehensive epigenomic analysis within H3K4me3- marked histone that allowed us to identify human neutrophil regulators affecting their plasticity during inflammation as well as suppression.

2021-10-27 | GSE186508 | GEO

Expression study between dental pulp cells from TRPC6-mut individual and control individuals

Project description:As TRPC6 channel induces CREB-mediated trancription, Dental pulp cells from TRPC6-mut patient and from 6 controls were analyzed in order to verify if the disruption of TRPC6 leads to transcriptional changes.

2014-10-23 | GSE62620 | GEO

Direct effects of IFNα on human CD8 T cells_without any other concomitant signals

Project description:IFNα-mediated gene expression pattern. Direct effects of IFNα on human CD8 T cells without any other concomitant signal. This analysis examined the direct effects of IFNa on human CD8 T cells without any other concomitant signal. Total human CD8 T cells were magnetically sorted from peripheral blood by negative selection. In order to minimize the presence of antigen-experienced cells, total human CD8 T cells were depleted of CD45RO+ cells by labelling with anti-CD45RO magnetic bead. In both steps of cellular sorting, negative selection were preferred to positive selection to avoid direct labelling of CD8 T cell surface molecules could interfere with downstream IFNa-mediated signalling. Magnetically sorted untouched human CD8+CD45R0- T cells from three different donors were unstimulated or stimulated with IFNa2b or IFNa5 and cells were harvested 7 hours later. mRNAs from the 3 subjects were pooled and analyzed using Affymetrix human HG-U133A 2.0 array gene chips Fold-change ≥ 2 criterion was used to identify genes which expression differed between treatment and control (unstimulated cells). Keywords: Gene expression pattern analysis Magnetically sorted untouched CD8+CD45R0-T cells mRNA pooled sample from three different donors unstimulated or stimulated with IFN alfa 2b or IFN alfa 5 for 7 hours.

2010-07-23 | E-GEOD-17299 | biostudies-arrayexpress

Protein profiling of stress-activated breast cancer cell models

Project description:This study provides insights into the efficacy of beta-blockers as breast cancer therapeutics.Cell line models of basal-type and estrogen receptor-positive breast cancer were profiled for basal levels of adrenoceptor gene/protein expression, and ADRβ2-mediated cell behaviour including migration, invasion, adhesion, and proliferation in response to adrenoceptor agonist/antagonist treatment. Protein profiling and histology identified response biomarkers and drug targets. Protein profiling revealed the upregulation of the pro-metastatic gene LYPD3 in norepinephrine treated MDA MB 468 cells. Histology confirmed selective LYPD3 expression in clinical primary and metastatic breast tumours. These findings demonstrate that basal-type cancer models show a more aggressive ADRβ2-activated phenotype in the resting and stimulated state, which is attenuated by ADRβ2 inhibition, and explain some of the previous studies that have cast doubt on the value of beta-blocker therapy in breast cancer. These findings suggest that propranolol should be clinically evaluated in patients with basal-type tumours expressing high levels of ADRβ2 and LYPD3.

2020-05-26 | PXD009488 | Pride

Acetylation level of Pannexin 1 lysine residues following alpha 1 adrenoceptor activation

Project description:Pannexin 1 (Panx1) channels can be activated by alpha 1 adrenoceptor-induced pathways for the sympathetic regulation of blood pressure; however, the molecular mechanisms for this form of Panx1 channel activation remain elusive. To identify potential acetyl-lysine residue(s) of Panx1 channels that might be involved in this receptor-mediated Panx1 channel activation, we performed mass-spectrometry on Strep-tagged Panx1 proteins precipitated from the whole cell lysate of HEK293T cells after stable isotope labeling by amino acids in cell culture (SILAC). Those HEK293T cells were transiently transfected with alpha1D adrenoceptors and human Panx1-Strep, with or without phenylephrine stimulation. Equal amounts of light-labeled (control) and heavy-labeled (phenylephrine stimulated) cell lysates were pooled, and Panx1 proteins were precipitated by Strep-Tactin beads, followed by LC-MS-MS analysis. From three biological replicates, we identified a consistent, albeit modest, reduction of acetylation level at K140, following phenylephrine stimulation. Whereas the acetylation level of other lysine residues (K321, K374, K381, K409) were variable among three replicates or were unaffected by phenylephrine treatment. These results implicate Panx1 K140 as a potential regulatory site for receptor-mediated channel activation via an acetylation-deacetylation mechanism.

2021-07-16 | PXD025912 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data