Endothelial‑to‑mesenchymal transition in human idiopathic dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and cardiac fibrosis. Emerging evidence indicated that endothelial-to-mesenchymal transition (Endo-MT) is a crucial event during organ fibrosis. This study was performed to clarify whether Endo-MT contributed to the progression of cardiac fibrosis in DCM. Cardiac samples from patients with DCM and control were obtained. The presence of endothelial markers, cluster of differentiation (CD)31 and vascular endothelial (VE)-cadherin, and mesenchymal markers, α smooth muscle actin (SMA) and fibroblast-specific protein 1 (FSP1) was performed using immunohistochemistry. Co-localization of endothelial markers and mesenchymal markers were identified using confocal immunofluorescence staining. Serum procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III amino-terminal propeptide (PIIINP) were measured by ELISA. Protein levels of Wnt, β-catenin and Snail were determined using western blot analysis. Immunohistochemistry and double-immunofluorescence staining demonstrated that the expression of CD31 and VE-cadherin were significantly decreased in DCM samples, whereas the FSP-1, and αSMA were significantly increased. CD31 and VE-cadherin labeling indexes were respectively negatively correlated with left ventricular end-diastolic diameter (LVEDD) (CD31 r=−0.82, P<0.01; VE-cadherin r=−0.73, P<0.01), while FSP-1 and αSMA were positively associated with LVEDD (αSMA r=0.65, P<0.01, FSP1 r=0.53, P<0.01) and left ventricular ejection fraction (αSMA r=−0.18, P<0.05; FSP1 r=−0.21, P<0.05). Furthermore, PICP and PIIINP levels were positively associated with the co-expression labeling indexes (CD31/SMA co-labeling index and PICP r=0.727, P<0.01; CD31/SMA co-labeling index and PIIINP r=0.741, P<0.01; VE-Cadherin/FSP-1 co-labeling index and PICP r=0.716, P<0.01; VE-cadherin/FSP-1 co-labeling index and PIIINP r=0.648, P<0.05). Western blot analysis indicated that proteins levels of Wnt signaling and snail were significantly increased in DCM samples. These results suggested that Endo-MT is potentially implicated in the pathogenesis of myocardial fibrosis and remodeling during the development of DCM, indicating a potential therapeutic target for DCM treatment.

BMP7 Ameliorated Viral Myocardial Fibrosis by Inhibiting Endothelial-to-Mesenchymal Transition

“…Previous findings have demonstrated the emergence of cardiac fibroblasts with an endothelial cell origin through Endo-MT in DCM patients [5]. One-third of the myofibroblasts was demonstrated to transdifferentiate from cells of endothelial origin in fibrotic heart [6,7,[23][24][25].…”

“…Smad4 translocates to the nucleus to regulate the transcription of target genes [22]. Furthermore, Wnt/β-catenin signaling was found to be activated to trigger Endo-MT in experimental myocardial infarction mice and DCM patients [5,34]. β-catenin was required for Endo-MT in heart cushion formation [35].…”

“…Accumulating studies have demonstrated that myocardial fibrosis orchestrates predominantly the development from VMC to DCM [2][3][4]. The emergence of cardiac fibroblasts with an endothelial cell origin, referred to as endothelial-tomesenchymal transition (Endo-MT), is associated with myocardial fibrosis in DCM [5]. Endo-MT is characterized by the loss of endothelial cell markers (CD31 and VE-cadherin) and acquisition of a mesenchymal phenotype (α-smooth muscle actin [α-SMA], fibroblast specific protein 1 [FSP-1]) [6,7].…”

“…Endo-MT is characterized by the loss of endothelial cell markers (CD31 and VE-cadherin) and acquisition of a mesenchymal phenotype (α-smooth muscle actin [α-SMA], fibroblast specific protein 1 [FSP-1]) [6,7]. To date, Endo-MT has emerged as a player in the pathogenesis of tissue fibrosis in various mouse models, including pressure overloaded [7], myocardial infarction [8], diabetes cardiomyopathy [9], dilated cardiomyopathy [5] and aging [10]. Furthermore, our data indicated that Endo-MT was induced by CVB3 infection in cardiac microvascular endothelial cells (CMVECs) in vitro [11].…”

Endocardial Endothelial Dysfunction and Unknown Polymorphic Composite Accumulation in Heart Failure

“…They have similar pathological characteristics, such as moderate to severe myofibril degeneration, vacuolation of the interstitial of the cardiac tissue, and fibrosis of cardiomyocytes through EndMT. EndMT contributes to the progression of HF through the activation of the Wnt and Snail signaling pathways and by increasing the expression of mesenchymal markers such as Wnt, β-catenin, and Snail [14,15]. In addition, accumulating evidence suggests that EndMT actively responds to valve injury, stress, and disease during heart valve development [10,16] and mediates valvular endothelial cell osteogenesis, leading to aortic valve calcification and mineral deposition [17].…”