Identification of intracellular proteins and signaling pathways in human endothelial cells regulated by angiotensin-(1–7)

Meinert, Christian; Gembardt, Florian; Böhme, Ilka; Tetzner, Anja; Wieland, Thomas; Greenberg, Barry; Walther, Thomas

doi:10.1016/j.jprot.2015.09.020

Cited by 14 publications

(12 citation statements)

References 45 publications

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“…This analysis suggests a possible convergence of the Ang-(1-7)/Mas1 receptor signaling in this study with previously known AngII/AT 1 R signaling, especially on the p38MAPK and ERK1/2 signal cascades, leading to upregulation of VEGFR signaling as indicated by downstream gene expression analysis (Figure 3). The Ang-(1-7)/Mas1 receptor signaling complex pathway data presented here is supported by previous literature showing that early stage changes in Ang-(1-7) induced phosphorylation and protein expression related to global changes in ERK1/2, AKT1, NFkB, and VEGF signaling 19, 20 and further confirm the molecular basis of the cell survival and anti-inflammatory role of Mas1 receptor activation.…”

Section: Resultssupporting

confidence: 90%

“…Additionally, the decreased detection of CARD10 following Ang-(1-7) stimulation suggests a downregulation of NFkB signaling and an anti-inflammatory response. This Ang-(1-7)/Mas1 receptor signaling complex pathway data is supported by previous literature showing that Ang-(1-7) induced global changes in phosphorylation and protein expression related to ERK1/2, AKT1, NFkB, and VEGF signaling 19, 20 . The direct signaling complex and pathways implicated by this dataset correlate with early stage, but not later stage, global alterations of phosphorylation detected in the previous phosphoproteomic study on Ang-(1-7) signaling 19 .…”

Section: Discussionsupporting

confidence: 88%

“…Studies involving human endothelial cells constitutively expressing the Mas1 receptor also suggest that Ang-(1-7) regulation of eNOS signaling may be occurring through the regulation of phosphatidylinositol 3-kinase (PI3K) and serine/threonine protein kinase AKT pathways 3, 10 . In addition, a study using quantitative phosphoproteomics provided insights into Ang-(1-7) induced phosphorylation changes 19 and a second study using an antibody-based protein assay to monitor Ang-(1-7) altered protein expression 20 in human endothelial cells. Both of these studies indicated global changes in signal transduction, apoptosis, cell cycle, and gene expression regulation.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Stodola

Wagner

Didier

et al. 2017

ATVB

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Objective Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1 (AT1R). Angiotensin 1-7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, while the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7). Approach and Results This study shows that low dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similarly to a low, subpressor dose of AngII acting through AT1R. Additionally, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Utilizing proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho Family GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen activated protein kinase (MAPK), and extracellular signal-related kinase (ERK) signaling. Further experimental antagonism of ERK1/2 and p38MAPK signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7). Conclusions These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII as compared to the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AT1R signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of MAPK/ERK signaling in maintaining vascular function.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Stodola

Wagner

Didier

et al. 2017

ATVB

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“…The need of such second messenger is also illustrated by the fact that 2 publications during the past years intensively investigated phosphorylation of intracellular molecules 28 and quantities of intracellular proteins, 29 respectively, in response to Ang-(1-7). Although aimed to identify useful molecules for receptor pharmacology, the data published failed to add useful tools to this approach.…”

Section: Discussionmentioning

confidence: 99%

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

et al. 2016

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Angiotensin (Ang)-(1–7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin–angiotensin system. Although it is well accepted that the G-protein–coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang-(1–7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1–7) allowing confirmation as well as discovery of the heptapeptide’s receptors. Ang-(1–7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1–7). Moreover, we identified the G-protein–coupled receptor MrgD as a second receptor for Ang-(1–7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in both Mas and MrgD . Mice deficient in MrgD showed an impaired hemodynamic response after Ang-(1–7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin–angiotensin system, by identifying a second receptor for Ang-(1–7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319.

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“…[1] in Table 1, Table 2, Table 3, Table 4. Here the name and ranking of the next regulated proteins are shown (Table 1, Table 2, Table 3, Table 4).…”

Section: Datamentioning

confidence: 99%

Further intracellular proteins and signaling pathways regulated by angiotensin-(1–7) in human endothelial cells

et al. 2017

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In 2016, Meinert et al. (doi: 10.1016/j.jprot.2015.09.020 10.1016/j.jprot.2015.09.020) published the first 25 proteins in a protein array regulated in Human Umbilical Vein Endothelial Cells (HUVEC) by the heptapeptide angiotensin (Ang)-(1–7) and the first 10 intracellular signaling cascades at different time points. This supporting data article shows further proteins and pathways stimulated by Ang-(1–7) in human endothelial cells at time points of 1 h, 3 h, 6 h, and 9 h. HUVECs were stimulated with Ang-(1–7), and regulated proteins were identified via antibody microarray. Bioinformatics software IPA was used for association of regulated proteins to metabolic pathways.

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Identification of intracellular proteins and signaling pathways in human endothelial cells regulated by angiotensin-(1–7)

Cited by 14 publications

References 45 publications

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

Further intracellular proteins and signaling pathways regulated by angiotensin-(1–7) in human endothelial cells

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