Ying Liang, Wojciech Ornatowski, Qing Lu, Xutong Sun, Manivannan Yegambaram, Anlin Feng, Yishu Dong, Saurabh Aggarwal, Hoshang J. Unwalla, Jeffrey R. Fineman, Stephen M. Black, Ting Wang
Florida International University. University of California, San Francisco.
United States
International Journal of Molecular Sciences
Int J Mol Sci 2025; 26:
DOI: 10.3390/ijms26031352
Abstract
Pulmonary arterial hypertension (PAH) is characterized by increased lung vascular stiffness and impaired vessel relaxation, primarily due to reduced nitric oxide (NO) production in endothelial cells. Recent studies indicate that chloroquine, an autophagy inhibitor, may help lower pulmonary arterial pressure and enhance lung vascular function. This study investigates the mechanisms underlying the chloroquine-mediated restoration of NO bioavailability in endothelial cells derived from aortopulmonary shunt lambs, a relevant model for congenital heart defect (CHD)-associated PAH. We found that NO production was significantly reduced in shunt pulmonary artery endothelial cells (PAECs), attributable to decreased levels of tetrahydrobiopterin (BH4) and diminished expression of GTP cyclohydrolase 1 (GCH1), despite a slight increase in endothelial nitric oxide synthase (eNOS) levels. Chloroquine robustly restored endothelial NO production, which correlated with increased BH4 levels and restored GCH1 expression. The mechanistically upregulated carboxyl terminus of Hsp70-interacting protein (CHIP) in shunt PAECs is responsible for heightened GCH1 degradation, and chloroquine disrupted the assembly of the GCH1-HSP70-CHIP complex to preserve cellular GCH1. Similarly, another autophagy inhibitor, bafilomycin A1, demonstrated comparable effects. These findings suggest that autophagy inhibition can effectively enhance NO synthesis in endothelial cells experiencing depleted NO bioavailability, presenting a potential therapeutic strategy for managing PAH.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes