LncRNA APF suppresses pulmonary vascular remodeling in chronic thromboembolic pulmonary hypertension through the miR-188-3p/ATG7-mediated autophagy pathway.

backgroundAn imbalance in autophagy leads to persistent pulmonary vascular remodeling, resulting from impaired phenotypes of dysfunctional vascular smooth muscle cells in chronic thromboembolic pulmonary hypertension (CTEPH). Long non-coding RNA autophagy-promoting factor (APF) is an essential regulator of the miR-188-3p/autophagy-related gene 7 (ATG7)/autophagy pathway in cardiomyocytes, but its role in CTEPH was uncertain.

methodsIn paired vascular specimens from CTEPH patients, APF/miR-188-3p/ATG7 expression changes were explored. Primary human pulmonary artery smooth muscle cells (HPASMCs) freshly isolated from CTEPH lesion sites were used for biological validation We investigated the effect of APF on the growth, migration, invasion ability, and autophagy of HPASMCs. Regulatory interactions along this axis were also verified. Rescue assays a using miR-188-3p inhibitor, ATG7 over-expression plasmids, and the autophagy inducer rapamycin were conducted to establish mechanistic connection.

resultsAPF and ATG7 were downregulated in CTEPH tissues, while miR-188-3p was upregulated. APF overexpression inhibited HPASMC proliferation, migration, and invasion but increased autophagy; APF knockdown showed the opposite effects. The pro-proliferative and pro-migratory behaviors induced by APF silencing or miR-188-3p upregulation were abrogated by inhibiting miR-188-3p or restoring ATG7, respectively. Reactivation of autophagy with rapamycin reversed the effects of APF silencing.

conclusionThe downregulation of APF in CTEPH promoted excessive proliferation, migration, and invasion in HPASMCs by inhibiting autophagy through the miR-188-3p/ATG7 axis. We highlight the APF/miR-188-3p/ATG7-autophagy pathway as a potential therapeutic target for CTEPH.