Abstract
Fibroblasts are responsible for producing the majority of collagen and other extracellular matrix (ECM) proteins in tissues. In the injured tissue, transforming growth factor-β (TGF-β)-activated fibroblasts or differentiated myofibroblasts synthesize excessive ECM proteins and play a pivotal role in the pathogenesis of fibrosis in heart, kidney and other organs. Recent studies suggest that fibroblast-like cells, derived from endothelial cells by endothelial-to-mesenchymal transition (EndMT), contribute to the pathogenesis of cardiac fibrosis. The molecular basis of EndMT, however, is poorly understood. Here, we investigated the molecular basis of EndMT in mouse cardiac endothelial cells (MCECs) in response to TGF-β2. MCECs exposed to TGF-β2 underwent EndMT as evidenced by morphologic changes, lack of acetylated-low density lipoprotein (Ac-LDL) uptake, and the presence of alpha-smooth muscle actin (α-SMA) staining. Treatment with SB431542, a small molecule inhibitor of TGF-β-receptor I (TβRI) kinase, but not PD98059, a MEK inhibitor, completely blocked TGF-β2-induced EndMT. The transcript and protein levels of α-SMA, Snail and β-catenin as well as acetyltransferase p300 (ATp300) were elevated in EndMT derived fibroblast-like cells. Importantly, microRNA (miRNA) array data revealed that the expression levels of specific miRNAs, known to be dysregulated in different cardiovascular diseases, were altered during EndMT. The protein level of cellular p53, a bonafide target of miR-125b, was downregulated in EndMT-derived fibroblast-like cells. Here, we report for the first time, the differential expression of miRNAs during cardiac EndMT. These results collectively suggest that TβRI serine-threonine kinase-induced TGF-β signaling and microRNAs, the epigenetic regulator of gene expression at the posttranscriptional level, are involved in EndMT and promote profibrotic signaling in EndMT-derived fibroblast-like cells. Pharmacologic agents that restrict the progression of cardiac EndMT, a phenomenon that is found in adults only in the pathological conditions, in targeting specific miRNA may be helpful in preventing and treating cardiac fibrosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1031-1036 |
| Number of pages | 6 |
| Journal | Cellular Signalling |
| Volume | 24 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2012 |
Fingerprint
Keywords
- ATp300
- Cardiac EndMT
- Epigenetics
- Fibrosis
- MicroRNA
- TβRI kinase
ASJC Scopus subject areas
- Cell Biology
Cite this
}
Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT) : Differential expression of microRNAs during EndMT. / Ghosh, Asish K; Nagpal, Varun; Covington, Joseph W.; Michaels, Marissa A.; Vaughan, Douglas E.
In: Cellular Signalling, Vol. 24, No. 5, 01.05.2012, p. 1031-1036.Research output: Contribution to journal › Article
TY - JOUR
T1 - Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT)
T2 - Differential expression of microRNAs during EndMT
AU - Ghosh, Asish K
AU - Nagpal, Varun
AU - Covington, Joseph W.
AU - Michaels, Marissa A.
AU - Vaughan, Douglas E
PY - 2012/5/1
Y1 - 2012/5/1
N2 - Fibroblasts are responsible for producing the majority of collagen and other extracellular matrix (ECM) proteins in tissues. In the injured tissue, transforming growth factor-β (TGF-β)-activated fibroblasts or differentiated myofibroblasts synthesize excessive ECM proteins and play a pivotal role in the pathogenesis of fibrosis in heart, kidney and other organs. Recent studies suggest that fibroblast-like cells, derived from endothelial cells by endothelial-to-mesenchymal transition (EndMT), contribute to the pathogenesis of cardiac fibrosis. The molecular basis of EndMT, however, is poorly understood. Here, we investigated the molecular basis of EndMT in mouse cardiac endothelial cells (MCECs) in response to TGF-β2. MCECs exposed to TGF-β2 underwent EndMT as evidenced by morphologic changes, lack of acetylated-low density lipoprotein (Ac-LDL) uptake, and the presence of alpha-smooth muscle actin (α-SMA) staining. Treatment with SB431542, a small molecule inhibitor of TGF-β-receptor I (TβRI) kinase, but not PD98059, a MEK inhibitor, completely blocked TGF-β2-induced EndMT. The transcript and protein levels of α-SMA, Snail and β-catenin as well as acetyltransferase p300 (ATp300) were elevated in EndMT derived fibroblast-like cells. Importantly, microRNA (miRNA) array data revealed that the expression levels of specific miRNAs, known to be dysregulated in different cardiovascular diseases, were altered during EndMT. The protein level of cellular p53, a bonafide target of miR-125b, was downregulated in EndMT-derived fibroblast-like cells. Here, we report for the first time, the differential expression of miRNAs during cardiac EndMT. These results collectively suggest that TβRI serine-threonine kinase-induced TGF-β signaling and microRNAs, the epigenetic regulator of gene expression at the posttranscriptional level, are involved in EndMT and promote profibrotic signaling in EndMT-derived fibroblast-like cells. Pharmacologic agents that restrict the progression of cardiac EndMT, a phenomenon that is found in adults only in the pathological conditions, in targeting specific miRNA may be helpful in preventing and treating cardiac fibrosis.
AB - Fibroblasts are responsible for producing the majority of collagen and other extracellular matrix (ECM) proteins in tissues. In the injured tissue, transforming growth factor-β (TGF-β)-activated fibroblasts or differentiated myofibroblasts synthesize excessive ECM proteins and play a pivotal role in the pathogenesis of fibrosis in heart, kidney and other organs. Recent studies suggest that fibroblast-like cells, derived from endothelial cells by endothelial-to-mesenchymal transition (EndMT), contribute to the pathogenesis of cardiac fibrosis. The molecular basis of EndMT, however, is poorly understood. Here, we investigated the molecular basis of EndMT in mouse cardiac endothelial cells (MCECs) in response to TGF-β2. MCECs exposed to TGF-β2 underwent EndMT as evidenced by morphologic changes, lack of acetylated-low density lipoprotein (Ac-LDL) uptake, and the presence of alpha-smooth muscle actin (α-SMA) staining. Treatment with SB431542, a small molecule inhibitor of TGF-β-receptor I (TβRI) kinase, but not PD98059, a MEK inhibitor, completely blocked TGF-β2-induced EndMT. The transcript and protein levels of α-SMA, Snail and β-catenin as well as acetyltransferase p300 (ATp300) were elevated in EndMT derived fibroblast-like cells. Importantly, microRNA (miRNA) array data revealed that the expression levels of specific miRNAs, known to be dysregulated in different cardiovascular diseases, were altered during EndMT. The protein level of cellular p53, a bonafide target of miR-125b, was downregulated in EndMT-derived fibroblast-like cells. Here, we report for the first time, the differential expression of miRNAs during cardiac EndMT. These results collectively suggest that TβRI serine-threonine kinase-induced TGF-β signaling and microRNAs, the epigenetic regulator of gene expression at the posttranscriptional level, are involved in EndMT and promote profibrotic signaling in EndMT-derived fibroblast-like cells. Pharmacologic agents that restrict the progression of cardiac EndMT, a phenomenon that is found in adults only in the pathological conditions, in targeting specific miRNA may be helpful in preventing and treating cardiac fibrosis.
KW - ATp300
KW - Cardiac EndMT
KW - Epigenetics
KW - Fibrosis
KW - MicroRNA
KW - TβRI kinase
UR - http://www.scopus.com/inward/record.url?scp=84857111170&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857111170&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2011.12.024
DO - 10.1016/j.cellsig.2011.12.024
M3 - Article
VL - 24
SP - 1031
EP - 1036
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 5
ER -