Am J Hypertens. 2026 Jun 3:hpag052. doi: 10.1093/ajh/hpag052. Online ahead of print.
ABSTRACT
BACKGROUND: Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) arises from chronic left-to-right shunting and high-flow exposure, leading to pulmonary vascular remodelling and right-heart dysfunction. Whether high-flow shunting induces branch-selective unfolded protein response (UPR) activation and endoplasmic reticulum (ER) structural adaptation in pulmonary vascular smooth muscle remains incompletely defined.
METHODS: Rats underwent right pulmonary artery ligation combined with left common carotid artery-external jugular vein shunting (RPAL/LCS), with or without 4-phenylbutyric acid (4-PBA) treatment. Hemodynamics, right-heart function, vascular remodeling, UPR signaling, transcriptomic profiles, apoptosis, and ER ultrastructure were assessed in vivo or in HPASMC gain- and loss-of-function experiments.
RESULTS: RPAL/LCS increased RVSP from 22.46 ± 1.68 to 59.66 ± 7.06 mmHg, whereas 4-PBA reduced RVSP to 38.24 ± 1.71 mmHg. The wall area/total vessel area ratio increased from 46.88 ± 1.69% to 77.89 ± 3.08% after RPAL/LCS and decreased to 47.19 ± 2.00% after 4-PBA treatment. Lung immunoblotting showed increased p-IRE1α/IRE1α, whereas p-PERK/PERK and ATF6N/ATF6 did not differ significantly; these proximal UPR markers were not reduced by 4-PBA at the endpoint. In HPASMCs, ATF4 and ATF6N overexpression enriched apoptosis-related programs and induced ER swelling and fragmentation, whereas XBP-1s overexpression maintained organized ER cisternae and XBP-1s knockdown disrupted ER ultrastructure with increased Annexin V-positive apoptotic cells.
CONCLUSIONS: This study suggests that the IRE1α-XBP1s axis supports adaptive ER proteostasis and structural organization in shunt-driven pulmonary hypertension, whereas 4-PBA improves disease features without measurable suppression of canonical UPR branch activation markers.
PMID:42234846 | DOI:10.1093/ajh/hpag052