ANG II activates effectors of mTOR via PI3-K signaling in human coronary smooth muscle cells

2004 ◽  
Vol 287 (3) ◽  
pp. H1232-H1238 ◽  
Author(s):  
Sassan Hafizi ◽  
Xuemin Wang ◽  
Adrian H. Chester ◽  
Magdi H. Yacoub ◽  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathway ◽  
Initiation Factor ◽  
Ang Ii ◽  
Eukaryotic Initiation Factor ◽  
Mtor Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Eukaryotic Initiation Factor 4E

We have previously shown that the vasoconstrictive peptide angiotensin II (ANG II) is a hypertrophic agent for human coronary artery smooth muscle cells (cSMCs), which suggests that it plays a role in vascular wall thickening. The present study investigated the intracellular signal transduction pathways involved in the growth response of cSMCs to ANG II. The stimulation of protein synthesis by ANG II in cSMCs was blocked by the immunosuppressant rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway that includes the 70-kDa S6 kinase (p70S6k) and plays a key role in cell growth. The inhibitory effect of rapamycin was reversed by a molar excess of FK506; this indicates that both agents act through the common 12-kDa immunophilin FK506-binding protein. ANG II caused a rapid and sustained activation of p70S6k activity that paralleled its phosphorylation, and both processes were blocked by rapamycin. In addition, both of the phosphatidylinositol 3-kinase inhibitors wortmannin and LY-294002 abolished the ANG II-induced increase in protein synthesis, and wortmannin also blocked p70S6k phosphorylation. Furthermore, ANG II triggered dissociation of the translation initiation factor, eukaryotic initiation factor-4E, from its regulatory binding protein 4E-BP1, which was also inhibited by rapamycin and wortmannin. In conclusion, we have shown that ANG II activates components of the rapamycin-sensitive mTOR signaling pathway in human cSMCs and involves activation of phosphatidylinositol 3-kinase, p70S6k, and eukaryotic initiation factor-4E, which leads to activation of protein synthesis. These signaling mechanisms may mediate the growth-promoting effect of ANG II in human cSMCs.

scholarly journals Phosphorylation of eukaryotic initiation factor 4E (eIF4E) at Ser209 is not required for protein synthesis in vitro and in vivo

2001 ◽  
Vol 268 (20) ◽  
pp. 5375-5385 ◽  
Author(s):  
Linda McKendrick ◽  
Simon J. Morley ◽  
Virginia M. Pain ◽  
Rosemary Jagus ◽  
Bhavesh Joshi
Keyword(s):  
Protein Synthesis ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E

Angiotensin II inhibits insulin-stimulated phosphorylation of eukaryotic initiation factor 4E-binding protein-1 in proximal tubular epithelial cells

2001 ◽  
Vol 360 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Duraisamy SENTHIL ◽  
Jennifer L. FAULKNER ◽  
Goutam GHOSH CHOUDHURY ◽  
Hanna E. ABBOUD ◽  
Balakuntalam S. KASINATH
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Insulin Signalling ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Tubular Epithelial Cells ◽  
Eukaryotic Initiation Factor 4E ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Stimulation Of

Interaction between angiotensin II, which binds a G-protein-coupled receptor, and insulin, a ligand for receptor tyrosine kinase, was examined in renal proximal tubular epithelial cells. Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) which follows the release of the factor from a heterodimeric complex by phosphorylation of its binding protein, 4E-BP1. Angiotensin II (1nM) or insulin (1nM) individually stimulated 4E-BP1 phosphorylation. However, pre-incubation with angiotensin II abrogated insulin-induced phosphorylation of 4E-BP1, resulting in persistent binding to eIF4E. Although angiotensin II and insulin individually activated phosphoinositide 3-kinase and extracellular signal-regulated kinase (ERK)-1/−2-type mitogen-activated protein (MAP) kinase, pre-incubation with angiotensin II abolished insulin-induced stimulation of these kinases, suggesting more proximal events in insulin signalling may be intercepted. Pretreatment with angiotensin II markedly inhibited insulin-stimulated tyrosine phosphorylation of insulin-receptor β-chain and insulin-receptor substrate 1. Losartan prevented angiotensin II inhibition of insulin-induced ERK-1/−2-type MAP kinase activation and 4E-BP1 phosphorylation, suggesting mediation of the effect of angiotensin II by its type 1 receptor. Insulin-stimulated de novo protein synthesis was also abolished by pre-incubation with angiotensin II. These data show that angiotensin II inhibits 4E-BP1 phosphorylation and stimulation of protein synthesis induced by insulin by interfering with proximal events in insulin signalling. Our data provide a mechanistic basis for insulin insensitivity induced by angiotensin II.

A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle

2003 ◽  
Vol 285 (6) ◽  
pp. C1437-C1444 ◽  
Author(s):  
Petra Rocic ◽  
Hanjoong Jo ◽  
Pamela A. Lucchesi
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Recombinant Adenovirus ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Initiation Factor ◽  
Cell Protein ◽  
Ang Ii ◽  
Tyrosine Kinase 2

Regulation of the PHAS-1-eukaryotic initiation factor-4E (eIF4E) complex is the rate-limiting step in the initiation of protein synthesis. This study characterized the upstream signaling pathways that mediate ANG II-dependent phosphorylation of PHAS-1 and eIF4E in vascular smooth muscle. ANG II-dependent PHAS-1 phosphorylation was maximal at 10 min (2.47 ± 0.3 fold vs. control). This effect was completely blocked by the specific inhibitors of phosphatidylinositol 3-kinase (PI3-kinase, LY-294002), mammalian target of rapamycin, and extracellular signal-regulated kinase 1/2 (ERK1/2, U-0126) or by a recombinant adenovirus encoding dominant-negative Akt. PHAS-1 phosphorylation was followed by dissociation of eIF4E. Increased ANG II-induced eIF4E phosphorylation was observed at 45 min (2.63 ± 0.5 fold vs. control), was maximal at 90 min (3.38 ± 0.3 fold vs. control), and was sustained at 2 h. This effect was blocked by inhibitors of the ERK1/2 and p38 mitogen-activated protein (MAP) kinase pathways, but not by PI3-kinase inhibition, and was dependent on PKC, intracellular Ca2+, and tyrosine kinases. Downregulation of proline-rich tyrosine kinase 2 (PYK2) by antisense oligonucleotides led to a near-complete inhibition of PHAS-1 and eIF4E phosphorylation in response to ANG II. Therefore, PYK2 represents a proximal signaling intermediate that regulates ANG II-induced vascular smooth muscle cell protein synthesis via regulation of the PHAS-1-eIF4E complex.

Kinin B1 receptor upregulation by angiotensin II and endothelin-1 in rat vascular smooth muscle cells: receptors and mechanisms

2010 ◽  
Vol 299 (5) ◽  
pp. H1625-H1632 ◽  
Author(s):  
Marielle Morand-Contant ◽  
Madhu B. Anand-Srivastava ◽  
Réjean Couture
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Protein Expression ◽  
Smooth Muscle Cells ◽  
Receptor Antagonist ◽  
Vascular Smooth Muscle Cells ◽  
Ang Ii ◽  
Phosphatidylinositol 3 Kinase

Oxidative stress upregulates the kinin B1 receptor (B1R) in diabetes and hypertension. Since angiotensin II (ANG II) and endothelin-1 (ET-1) are increased in these disorders, this study aims at determining the role of these two prooxidative peptides in B1R expression in rat vascular smooth muscle cells (VSMC). In the A10 cell line and aortic VSMC, ANG II enhanced B1R protein expression in a concentration- and time-dependent manner (maximal at 1 μM and 6 h). In A10 cells, ANG II (1 μM) also increased B1R mRNA expression at 3 h and the activation of induced B1R with the agonist [Sar-d-Phe8]-des-Arg9-BK (10 nM, 5 min) significantly enhanced mitogen -activated protein kinase (MAPK1/2) phosphorylation. The enhancing effect of ANG II on B1R protein expression in A10 cells was normalized by the AT1 (losartan) but not by the AT2 (PD123319) receptor antagonist. Furthermore, it was inhibited by inhibitors of phosphatidylinositol 3-kinase (wortmannin) and NF-κB (MG132) but not of MAPK (PD098059). Whereas the ETB receptor antagonist (BQ788) had no effect, the ETA receptor antagonist (BQ123) blocked the effect of ANG II at 6–8 h but not at an early time point. BQ123 and BQ788 also blocked the increasing effect of ET-1 on B1R protein expression. Antioxidants ( N-acetyl-l-cysteine and diphenyleneiodonium) abolished ANG II- and ET-1-increased B1R protein expression. In conclusion, B1R induction is linked to oxidative stress and activation of phosphatidylinositol 3-kinase and NF-κB. The newly synthesized B1R is functional and can activate MAPK signaling in VSMC. The effect of ANG II is mediated by the AT1 receptor and the subsequent activation of ETA through ET-1 release.

Kv1.3 channels modulate human vascular smooth muscle cells proliferation independently of mTOR signaling pathway

2014 ◽  
Vol 467 (8) ◽  
pp. 1711-1722 ◽  
Author(s):  
Pilar Cidad ◽  
Eduardo Miguel-Velado ◽  
Christian Ruiz-McDavitt ◽  
Esperanza Alonso ◽  
Laura Jiménez-Pérez ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathway ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Kv1.3 Channels

EGF receptor transactivation is obligatory for protein synthesis stimulation by G protein-coupled receptors

2002 ◽  
Vol 283 (2) ◽  
pp. C446-C455 ◽  
Author(s):  
Laure Voisin ◽  
Sylvain Foisy ◽  
Edith Giasson ◽  
Chantal Lambert ◽  
Pierre Moreau ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
G Protein ◽  
Muscle Cells ◽  
G Protein Coupled Receptors ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Egfr Transactivation ◽  
G Protein Coupled

The epidermal growth factor receptor (EGFR) was recently identified as a signal transducer of G protein-coupled receptors (GPCRs). In this study, we have examined the contribution of EGFR transactivation to the growth-promoting effect of GPCRs on vascular smooth muscle cells. Activation of the Gq-coupled ANG II receptor or Gi-coupled lysophosphatidic acid receptor resulted in increased tyrosine phosphorylation and activation of EGFR. Specific inhibition of EGFR kinase activity by tyrphostin AG-1478 or expression of a dominant-negative EGFR mutant abolished this response. Importantly, inhibition of EGFR function strongly attenuated the global stimulation of protein synthesis by GPCR agonists in vitro in cultured aortic smooth muscle cells and in vivo in the rat aorta and in small resistance arteries. The growth inhibition was associated with a marked reduction of extracellular signal-regulated kinase and phosphoinositide 3-kinase pathway activity and the resulting suppression of eukaryotic translation initiation factor 4E and 4E binding protein 1 phosphorylation. Our results demonstrate that EGFR transactivation is a physiologically relevant action of GPCRs linked to translational control and protein synthesis.

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