Endoglin Modulation of TGF-ß1-Induced Collagen Synthesis is Dependent on ERK1/2 MAPK Activation

Abstract

Background/Aims: Transforming growth factor-β1 (TGF-β1) plays a pivotal role in the extracellular matrix accumulation observed in fibrotic diseases. Endoglin is an important component of the TGF-β receptor complex highly expressed in tissues undergoing fibrotic processes. Endoglin expression regulates the effect of TGF-β on extracellular matrix synthesis. The purpose of our study has been to understand the molecular mechanism by which endoglin exerts its effects on fibrosis and the possible role of MAP kinases in these effects. Methods: We have assessed in mock and in endoglin-transfected L6E9 myoblasts the effect of TGF-β1 on collagen mRNA by Northern blot and effect of TGF-β1 on collagen content in the cultured medium by [³H]-Proline incorporation into collagen proteins. Total and activated MAPK and their role on collagen synthesis were assessed by Western blot. Results: TGF-β1 induced an increase on α₂ (I) collagen mRNA expression and collagen accumulation in mock-transfected myoblasts, whereas the response was much lower in endoglintransfected cells. TGF-β1 activated the ERK1/2 and p38 MAPK pathways but not the JNK pathway in L6E9 myoblasts. TGF-β1-induced α₂ (I) collagen mRNA expression and collagen accumulation were completely inhibited by SB203580, in either mock or endoglintransfected myoblasts. PD98059 increased TGF-β1 induced-collagen synthesis and accumulation in endoglin-transfected myoblasts but not in mock cells. Conclusion: Our studies demonstrate that TGF-β1- induced collagen synthesis is mediated by p38 MAPK activation in L6E9 myoblasts. Furthermore, endoglin expression reduces basal and TGF-β1 induced collagen synthesis when ERK1/2 pathway is operating.

Endoglin is involved in BMP‐2‐induced osteogenic differentiation of periodontal ligament cells through a pathway independent of Smad‐1/5/8 phosphorylation

“…It should be also noted that endoglin is involved in cell adhesion, cell migration (Bernabeu et al, 2007), and the synthesis of matrix proteins such as collagen (Rodríguez-Barbero et al, 2006). Adhesion molecules and matrix proteins play an important role in osteoblast functions and bone remodeling (Damsky, 1999;Bennett et al, 2001); thus investigation from this point of view should be also necessary to elucidate mechanisms underlying our findings.…”

MicroRNA-208a Increases Myocardial Endoglin Expression and Myocardial Fibrosis in Acute Myocardial Infarction

“…Endoglin is a potent mediator of profibrotic effects of angiotensin II on cardiac fibroblasts and can modulate the effect of TGF-b1 on extracellular matrix synthesis. 18,19 In this study, we have demonstrated that pretreatment with valsartan, an angiotensin-receptor antagonist, can reduce myocardial fibrosis through reducing endoglin expression after MI. The effect of inhibition of miR-208a induced by MI occurred earlier with valsartan than with atorvastatin because valsartan, but not atorvastatin, had an inhibitory effect on miR208a expression after 3 days of AMI.…”

“…17 Endoglin is a potent mediator of profibrotic effects of angiotensin II on cardiac fibroblasts and can modulate the effect of TGF-b1 on extracellular matrix synthesis. 18,19 These data indicate that endoglin may play an important role in fibrogenesis in cardiac remodelling. We have previously demonstrated that miR-208a can increase endoglin expression in cardiac myoblasts and in volume-overloading heart failure to modulate myocardial fibrosis.…”

DOCA and TGF-β Induce Early Growth Response Gene-1 (Egr-1) Expression

“…Activation of the renin-angiotensinaldosterone system (RAAS) stimulates transforming growth factor-β (TGF-β) expression in the kidney through various mechanisms and upregulates receptors for TGF-β. TGF-β is one of the key factors stimulating synthesis of collagen and other extracellular matrix components [8,9]. Recent findings show that TGF-β induces a rapid but transient accumulation of Egr-1 transcripts and protein in human skin fibroblasts [10].…”