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Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis

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ABSTRACT

Emerging evidence has suggested the critical role of endothelial to mesenchymal transition (EndMT) in fibrotic diseases. The present study was designed to examine whether EndMT is involved in arsenic trioxide (As2O3)-induced cardiac fibrosis and to explore the underlying mechanisms. Cardiac dysfunction was observed in rats after exposure to As2O3 for 15 days using echocardiography, and the deposition of collagen was detected by Masson’s trichrome staining and electron microscope. EndMT was indicated by the loss of endothelial cell markers (VE-cadherin and CD31) and the acquisition of mesenchymal cell markers (α-SMA and FSP1) determined by RT-PCR at the mRNA level and Western blot and immunofluorescence analysis at the protein level. In the in-vitro experiments, endothelial cells acquired a spindle-shaped morphology accompanying downregulation of the endothelial cell markers and upregulation of the mesenchymal cell markers when exposed to As2O3. As2O3 activated the AKT/GSK-3β/Snail signaling pathway, and blocking this pathway with PI3K inhibitor (LY294002) abolished EndMT in As2O3-treated endothelial cells. Our results highlight that As2O3 is an EndMT-promoting factor during cardiac fibrosis, suggesting that targeting EndMT is beneficial for preventing As2O3-induced cardiac toxicity.

No MeSH data available.


Effect of As2O3 on cardiac function determined by echocardiography.(a) Representative echocardiographic photos from M-mode. (b) Ejection fraction (EF) in each group. (c) Fraction shortening (FS) in each group. (d) Left ventricular end-diastolic volume (LVEDV) in each group. (e) Ratio of peak early diastolic ventricular filling velocity to peak atrial filling velocity (E/A). n = 4–5 rats in each group. *p < 0.05, **p < 0.01, ***p < 0.001 vs. Control.
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f1: Effect of As2O3 on cardiac function determined by echocardiography.(a) Representative echocardiographic photos from M-mode. (b) Ejection fraction (EF) in each group. (c) Fraction shortening (FS) in each group. (d) Left ventricular end-diastolic volume (LVEDV) in each group. (e) Ratio of peak early diastolic ventricular filling velocity to peak atrial filling velocity (E/A). n = 4–5 rats in each group. *p < 0.05, **p < 0.01, ***p < 0.001 vs. Control.

Mentions: The adverse effects of As2O3 on the heart have been reported in both clinical practice and basic research2425. After two weeks of As2O3 administration, we performed echocardiographic measurements to evaluate the effect of As2O3 on cardiac function. The corresponding echocardiographic images in the control group and As2O3-treated groups (0.4 mg/kg, 0.8 mg/kg, 1.6 mg/kg) are shown in Fig. 1a. The ejection fraction (EF%) declined significantly from 82.83 ± 3.72% for control to 59.68 ± 4.21%, 60.57 ± 0.90% and 58.44 ± 1.06% for varying dosages of As2O3, respectively (Fig. 1b). Moreover, the fractional shortening (FS%) decreased dramatically from 53.03 ± 4.61% to 32.73 ± 2.96%, 33.33 ± 0.71% and 31.55 ± 0.73%, respectively (Fig. 1c). Additionally, we detected left ventricular end-diastolic volume (LVEDV) and ratio of peak early diastolic ventricular filling velocity to peak atrial filling velocity (E/A), which can be used as indicative markers of diastolic dysfunction. The results in Fig. 1d–e showed that LVEDV was elevated, while the E/A ratio was declined after exposure to As2O3. But this effect was only statistically significant at the dosages of 1.6 mg/kg and 0.8 mg/kg. The detailed data for end-systolic and end-diastolic volumes and other additional parameters were also provided (Supplementary Table 2). All of these data indicated that cardiac dysfunction appeared when the rats received As2O3 treatment.


Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis
Effect of As2O3 on cardiac function determined by echocardiography.(a) Representative echocardiographic photos from M-mode. (b) Ejection fraction (EF) in each group. (c) Fraction shortening (FS) in each group. (d) Left ventricular end-diastolic volume (LVEDV) in each group. (e) Ratio of peak early diastolic ventricular filling velocity to peak atrial filling velocity (E/A). n = 4–5 rats in each group. *p < 0.05, **p < 0.01, ***p < 0.001 vs. Control.
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f1: Effect of As2O3 on cardiac function determined by echocardiography.(a) Representative echocardiographic photos from M-mode. (b) Ejection fraction (EF) in each group. (c) Fraction shortening (FS) in each group. (d) Left ventricular end-diastolic volume (LVEDV) in each group. (e) Ratio of peak early diastolic ventricular filling velocity to peak atrial filling velocity (E/A). n = 4–5 rats in each group. *p < 0.05, **p < 0.01, ***p < 0.001 vs. Control.
Mentions: The adverse effects of As2O3 on the heart have been reported in both clinical practice and basic research2425. After two weeks of As2O3 administration, we performed echocardiographic measurements to evaluate the effect of As2O3 on cardiac function. The corresponding echocardiographic images in the control group and As2O3-treated groups (0.4 mg/kg, 0.8 mg/kg, 1.6 mg/kg) are shown in Fig. 1a. The ejection fraction (EF%) declined significantly from 82.83 ± 3.72% for control to 59.68 ± 4.21%, 60.57 ± 0.90% and 58.44 ± 1.06% for varying dosages of As2O3, respectively (Fig. 1b). Moreover, the fractional shortening (FS%) decreased dramatically from 53.03 ± 4.61% to 32.73 ± 2.96%, 33.33 ± 0.71% and 31.55 ± 0.73%, respectively (Fig. 1c). Additionally, we detected left ventricular end-diastolic volume (LVEDV) and ratio of peak early diastolic ventricular filling velocity to peak atrial filling velocity (E/A), which can be used as indicative markers of diastolic dysfunction. The results in Fig. 1d–e showed that LVEDV was elevated, while the E/A ratio was declined after exposure to As2O3. But this effect was only statistically significant at the dosages of 1.6 mg/kg and 0.8 mg/kg. The detailed data for end-systolic and end-diastolic volumes and other additional parameters were also provided (Supplementary Table 2). All of these data indicated that cardiac dysfunction appeared when the rats received As2O3 treatment.

View Article: PubMed Central - PubMed

ABSTRACT

Emerging evidence has suggested the critical role of endothelial to mesenchymal transition (EndMT) in fibrotic diseases. The present study was designed to examine whether EndMT is involved in arsenic trioxide (As2O3)-induced cardiac fibrosis and to explore the underlying mechanisms. Cardiac dysfunction was observed in rats after exposure to As2O3 for 15&thinsp;days using echocardiography, and the deposition of collagen was detected by Masson&rsquo;s trichrome staining and electron microscope. EndMT was indicated by the loss of endothelial cell markers (VE-cadherin and CD31) and the acquisition of mesenchymal cell markers (&alpha;-SMA and FSP1) determined by RT-PCR at the mRNA level and Western blot and immunofluorescence analysis at the protein level. In the in-vitro experiments, endothelial cells acquired a spindle-shaped morphology accompanying downregulation of the endothelial cell markers and upregulation of the mesenchymal cell markers when exposed to As2O3. As2O3 activated the AKT/GSK-3&beta;/Snail signaling pathway, and blocking this pathway with PI3K inhibitor (LY294002) abolished EndMT in As2O3-treated endothelial cells. Our results highlight that As2O3 is an EndMT-promoting factor during cardiac fibrosis, suggesting that targeting EndMT is beneficial for preventing As2O3-induced cardiac toxicity.

No MeSH data available.