TGF-β-induced autophagy in pulmonary artery endothelial cells associated with chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive vascular disorder characterized by persistent thromboembolic obstruction and fibrotic remodeling of the pulmonary arteries. Although autophagy has been implicated in various forms of pulmonary hypertension, its specific role in CTEPH pathogenesis remains unclear. In this study, histological, immunohistochemical, and molecular analyses of pulmonary artery lesions from CTEPH patients revealed increased collagen deposition and elevated expression of autophagy markers beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3) compared to non-CTEPH controls. Primary pulmonary artery endothelial cells (PAECs) derived from CTEPH patients exhibited dysregulated autophagy-related protein expression. Mechanistically, TGF-β stimulation induced autophagy via the Smad3 signaling pathway. Notably, riociguat, a soluble guanylate cyclase stimulator approved for CTEPH, modulated autophagy-related proteins in vitro. In hypoxia- and TGF-β-induced pulmonary hypertension mouse models, riociguat attenuated LC3 but not beclin-1 expression and significantly reduced right ventricular systolic pressure. These findings suggest that LC3 may be a key autophagy marker in CTEPH. These findings identify the TGF-β/Smad3-LC3 axis as a critical mechanism driving CTEPH and suggest that pharmacological modulation of autophagy, particularly via riociguat, offers a promising therapeutic opportunity, especially for patients ineligible for surgical intervention. KEY MESSAGES: Beclin-1 and LC3, key autophagy markers, are upregulated in thrombofibrotic pulmonary arteries from patients with CTEPH. TGF-β activates autophagy in pulmonary artery endothelial cells through the Smad3 signaling pathway. Riociguat treatment downregulates LC3 expression, improves pulmonary hemodynamics, and reduces vascular remodeling in experimental PH models. LC3 as a potential biomarker and therapeutic target in the progression of CTEPH driven by autophagy.