Akt promotes Endocardial-Mesenchyme Transition

Meadows, Kafi N.; Iyer, Seema; Stevens, Mark V.; Wang, Duanning; Shechter, Sharon; Perruzzi, Carole; Camenisch, Todd D.; Benjamin, Laura E.

doi:10.1186/2040-2384-1-2

Cited by 41 publications

(44 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…97,98 PTEN also negatively regulates Akt/PKB activation, which has been implicated in EMT [99][100][101][102][103][104] as well as in EndMT. 85,105 Consistent with ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Section: Role Of Mir-21 In Epithelial-to-mesenchymal Transition and Fsupporting

confidence: 60%

Regulation and function of miRNA-21 in health and disease

2011

View full text Add to dashboard Cite

Section: Role Of Mir-21 In Epithelial-to-mesenchymal Transition and Fsupporting

confidence: 60%

Regulation and function of miRNA-21 in health and disease

2011

View full text Add to dashboard Cite

“…Indeed, Akt activation plays an important role in both EMT 29,31 and EndMT. 8,34,35 Expression of PTEN, which is one of the best validated targets of miR-21, 21,51 decreases after treatment with TGF-␤. 52 Loss of PTEN expression has been linked with Akt activation 53 and EMT.…”

Section: Discussionmentioning

confidence: 99%

“…Similar results were observed in endothelial cells of murine origin (Supplemental Figure III). Akt activation plays dominant roles in both EMT [25][26][27][28][29][30][31][32][33] and EndMT 8,34,35 processes. We thus examined alterations in the expression of endothelial markers after TGF-␤ treatment alone or during pharmacological Akt inhibition.…”

Section: Arterioscler Thromb Vasc Biol February 2012mentioning

confidence: 99%

“…20 Phosphatase and tensin homolog (PTEN), which is a well-established target of miR-21, 21,22 has been described as a negative regulator of EMT, 23,24 as well as Akt activation, which is involved in both EMT [25][26][27][28][29][30][31][32][33] and EndMT. 8,34,35 Therefore, we here hypothesized that miR-21 plays an important role in the process of EndMT via targeting the PTEN/Akt pathway.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Transforming Growth Factor-β–Induced Endothelial-to-Mesenchymal Transition Is Partly Mediated by MicroRNA-21

Kumarswamy

Volkmann

Jazbutyte

et al. 2012

ATVB

270

186

View full text Add to dashboard Cite

Objective— MicroRNAs are a class of small ribonucleotides regulating gene/protein targets by transcript degradation or translational inhibition. Transforming growth factor-β (TGF-β) is involved in cardiac fibrosis partly by stimulation of endothelial-to-mesenchymal transition (EndMT). Here, we investigated whether microRNA (miR)-21, a microRNA enriched in fibroblasts and involved in general fibrosis, has a role in cardiac EndMT. Methods and Results— TGF-β treatment of endothelial cells significantly increased miR-21 expression and induced EndMT characterized by suppression of endothelial and increase of fibroblast markers. Overexpression of miR-21 alone also stimulated EndMT. Importantly, miR-21 blockade by transfection of specific microRNA inhibitors partly prevented TGF-β-induced EndMT. Mechanistically, miR-21 silenced phosphatase and tensin homolog in endothelial cells, resulting in activation of the Akt-pathway. Akt inhibition partly restored TGF-β-mediated loss of endothelial markers during EndMT. In vivo, pressure overload of the left ventricle led to increased expression of miR-21 in sorted cardiac endothelial cells, which displayed molecular and phenotypic signs of EndMT. This was attenuated by treatment of mice subjected to left ventricular pressure overload with an antagomir against miR-21. Conclusion— TGF-β-mediated EndMT is regulated at least in part by miR-21 via the phosphatase and tensin homolog/Akt pathway. In vivo, antifibrotic effects of miR-21 antagonism are partly mediated by blocking EndMT under stress conditions.

show abstract

“…The tetracycline response elements-RTEF-1/LacZ construct was microinjected into fertilized mouse eggs. The endothelial-specific expression transgenic mouse, VE-Cadherin:RTEF-1, was obtained by crossing the endothelial-specific driver line (VE-Cadherin:tTA) (from Dr Laura Benjamin, BIDMC) 16 and responder line (tetracycline response elements-RTEF-1/LacZ). Double transgenic mice were genotyped by polymerase chain reaction with primers specific for tTA and RTEF-1.…”

Section: Generation Of Endothelial-specific Rtef-1 Transgenic Modelsmentioning

confidence: 99%

Endothelial Cells Require Related Transcription Enhancer Factor-1 for Cell–Cell Connections Through the Induction of Gap Junction Proteins

Jin

Philbrick

et al. 2012

ATVB

View full text Add to dashboard Cite

Objective-Capillary network formation represents a specialized endothelial cell function and is a prerequisite to establish a continuous vessel lumen. Formation of endothelial cell connections that form the vascular structure is regulated, at least in part, at the transcriptional level. We report here that related transcription enhancer factor-1 (RTEF-1) plays an important role in vascular structure formation. Methods and Results-Knockdown of RTEF-1 by small interfering RNA or blockage of RTEF-1 function by the transcription enhancer activators domain decreased endothelial connections in a Matrigel assay, whereas overexpression of RTEF-1 in endothelial cells resulted in a significant increase in cell connections and aggregation. In a model of oxygen-induced retinopathy, endothelial-specific RTEF-1 overexpressing mice had enhanced angiogenic sprouting and vascular structure remodeling, resulting in the formation of a denser and more highly interconnected superficial capillary plexus. Mechanistic studies revealed that RTEF-1 induced the expression of functional gap junction proteins including connexin 43, connexin 40, and connexin 37. Blocking connexin 43 function inhibited RTEF-1-induced endothelial cell connections and aggregation. We further found that gap junction proteins, specifically connexin (Cx) 37, Cx40, and Cx43, were significantly regulated by RTEF-1 and acted as adhesion sites that enhanced endothelial cellular connections and aggregation, as well as promoted the timely formation of competent vascular networks. We selected a mouse retina model for our in vivo studies because of the retinal vasculature developing shortly after birth in a highly stereotypic manner, 9 and RTEF-1 appeared as an essential gene for retinal vascular development by enhancing angiogenic sprouting and promoting the formation of a denser primary capillary network in an oxygen-induced retinopathy (OIR) model. These observations indicate that RTEF-1 coordinated endothelial cell-to-cell connections and is essential for the assembly of vascular networks in vitro and in vivo. Materials and Methods Cell CultureHuman umbilical vein endothelial cells (Lonza, Allendale, NJ) were cultured in endothelial basal medium-2 (Lonza). Human microvascular endothelial cells-1 (HMEC-1, Center for Disease Control and Prevention, Atlanta, GA) were cultured in MCDB-131 (Invitrogen, Carlsbad, CA). HMEC-1 is an immortalized HMEC line that retains the morphological, phenotypic, and functional characteristics of normal HMEC.10 Human embryonic kidney 293 and 293T were cultured in DMEM (Invitrogen). Retroviral Transduction and Small Interfering RNA TransfectionThe coding sequence of RTEF-1 (NM_003213) was subcloned from a PXJ40/RTEF-1 construct (a gift from Dr Alexandre Stewart, University of Ottawa) into the pBMN-GFP vector (Orbigen, San Diego, CA) to produce pBMN-GFP-RTEF-1. 293T cells were transfected with pBMN-GFP (or pBMN-GFP-RTEF-1), pMD-VSVG, pJK3, and pCMV-tat using Polyethylenimine (Polysciences, Warrington, PA) as previously reported 11 to a packag...

show abstract

Akt promotes Endocardial-Mesenchyme Transition

Cited by 41 publications

References 27 publications

Regulation and function of miRNA-21 in health and disease

Regulation and function of miRNA-21 in health and disease

Transforming Growth Factor-β–Induced Endothelial-to-Mesenchymal Transition Is Partly Mediated by MicroRNA-21

Endothelial Cells Require Related Transcription Enhancer Factor-1 for Cell–Cell Connections Through the Induction of Gap Junction Proteins

Contact Info

Product

Resources

About