Galectin-3 Mediates Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Abstract

Galectin-3 (Gal-3) is highly expressed in fibrotic tissue related to diverse etiologies. endothelial-to-mesenchymal transition (EndoMT), A less well studied phenomenon serves as a critical process in pulmonary vascular remodeling associated with the development of pulmonary arterial hypertension (PAH). EndoMT is hypothesized to contribute to the over-proliferation of αSMA positive cells. We aim to investigate the potential role of Gal-3 in regulating EndoMT in PAH. We observed an upregulation in both Gal-3 and αSMA expression in the monocrotaline (MCT) and Hypoxia PAH model, accompanied with intimal thickening. For more profound vascular remodeling and endothelial layer lesion in former model, we employed Gal-3 knockdown and overexpression lentivirus methodology to the MCT rats to determine the mechanisms underlying abnormal endothelial cell transition in PAH. PAH was evaluated according to right ventricular systolic pressure, right heart hypertrophy and pulmonary artery remodeling. A reduction in Gal-3 was protective against the development of PAH, while Gal-3 upregulation aggravated pulmonary vascular occlusion. In addition, Gal-3 deficiency suppressed pulmonary vascular cell proliferation and macrophage infiltration. Finally, we revealed that in endothelial cells treated with tumor necrosis factor α and hypoxia (representing an in vitro model of PAH), inhibition of Gal-3 by siRNA was able to abolish the associated upregulation of αSMA. These observations suggesting Gal-3 serves as a critical mediator in PAH by regulating EndoMT. Inhibition of Gal-3 may represent a novel therapeutic target for PAH treatment.

Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

“…Saline was given to the control group as placebo. For the other four groups, MCT (60 mg/kg) [24,25] was injected into the subcutaneous tissue to induce progressive pulmonary arterial hypertension at the end of 21 days.…”

“…Right ventricular systolic pressure (RVSP) was measured through the right jugular vein by a precurved catheter. Hemodynamic data were recorded and analyzed with a PowerLab Data Acquisition system (AD Instruments) [24]. The right lung and heart tissues were flushed with saline to clear blood and snap frozen in liquid nitrogen and stored at -80°C in preparation for Western blot analysis.…”

“…Morphometric analyses were performed on pulmonary arteries with an external diameter between 50 and 100 μm. Medial thickness was calculated using the following formula: medial thickness ð%Þ = medial wall thickness/external diameter × 100 [24,26]. For quantitative analyses, 30 small pulmonary vessels from each animal that were less than 50 μm in external diameter were evaluated for muscularization [24].…”

“…Medial thickness was calculated using the following formula: medial thickness ð%Þ = medial wall thickness/external diameter × 100 [24,26]. For quantitative analyses, 30 small pulmonary vessels from each animal that were less than 50 μm in external diameter were evaluated for muscularization [24]. Elastic staining was conducted according to the manufacturer's protocol (Sigma-Aldrich® Elastic Stain Procedure No.…”

Trimethoxystilbene Reduces Nuclear Factor Kappa B, Interleukin-6, and Tumor Necrosis Factor-αLevels in Rats with Pulmonary Artery Hypertension

“…PAH is a group of major pulmonary vascular diseases characterized by a progressive increase in pulmonary artery pressure [11]. An average pulmonary artery pressure >25 mmHg under resting conditions or >30 mmHg during movement with a corresponding pulmonary capillary wedge pressure (PCWP) < 15 mmHg constitutes a diagnosis of PAH.…”