The Role of Endoglin in Myocardial Fibrosis

Abstract

Myocardial fibrosis is closely associated with heart failure because myocardial fibrosis may cause the loss of normal cardiac function. Endoglin is a homeodimeric membrane glycoprotein, a co-receptor of transforming growth factor-β1 (TGF-β1) and β3. Endoglin is a potent mediator of profibrotic effects of angiotensin II on cardiac fibroblasts and can modulate the effect of TGF-β1 on extracellular matrix synthesis. These data indicate that endoglin plays an important role in fibrogenesis in cardiac remodeling. Endoglin induced by TGF-β1 is largely through PI-3 kinase, Akt, Smad3/4 and endoglin promoter pathways. Endoglin was upregulated in pressure- overload, volume-overload heart failure and acute myocardial infarction and was associated with myocardial fibrosis. Silencing endoglin expression could attenuate myocardial fibrosis and improve survival in animal study. Endoglin expression was increased in failing left ventricle before use of left ventricle assist device, and reduced back to control levels after use of left ventricle assist device. Targeting endoglin may provide a potentially unique and novel therapeutic approach for reducing myocardial fibrosis in patients with heart failure.

Keywords: Angiotensin II; Endoglin; MicroRNA; Myocardial fibrosis; TGF-β1.

Figure 1

The interplay of TGF-β1 and endoglin to induce cardiac fibrosis in cardiac fibroblast. Angiotensin II (Ang II) increases TGF-β1 expression through AT1 receptor. The increased TGF-β1 activates endoglin expression through PI-3 kinase, Akt, and Smad3/4. The increased endoglin increases collagen I to induce myocardial fibrosis. Atorvastatin could inhibit PI-3 kinase phosphorylation and then reduced endoglin expression to improve myocardial fibrosis.

Figure 2

The interplay between mechanical stretch, TGF-β1, and miR-208a in cardiac myoblasts. Mechanical stretch increases TGF-β1 secretion and then TGF-β1 increases smad/3/4 phosphorylation to increase miR208a promoter activity. The increased miR208a activates endoglin and collagen I expression to induce myocardial fibrosis. The endoglin promoter sequences have specific sites that are complementary to miR-208a. Soluble endoglin could antagonize TGF-β1 signaling. Antagomir 208a could antagonize miR208a and then reduce endoglin expression to improve myocardial fibrosis.

Figure 3

Proposed pathway of acute myocardial infarction (AMI) and volume overload heart failure (VOHF) model to induce myocardial fibrosis. AMI and VOHF could increase miR-208a expression and then activate endoglin expression to induce myocardial fibrosis. Atorvastatin and valsartan could attenuate miR-208a expression and the attenuated miR-208a reduces endoglin expression and finally improves myocardial fibrosis.