Genome-wide network analysis identifies the lncRNA-92467/miR-205-5p/PTPRM/CAMs axis in a rat model of hypoxic...

Hypoxic pulmonary hypertension (HPH) is a progressive chronic disorder characterized by elevated mean pulmonary arterial pressure. It severely impairs right ventricular function and ultimately causes right ventricular failure. Clarifying the complex pathogenesis of HPH remains a critical challenge.

Rat HPH models were established by exposure to a hypobaric hypoxia chamber for 4 consecutive weeks. Lung tissues were harvested for RNA sequencing. The Coding-Non-Coding Index (CNCI) and Coding Potential Calculator (CPC) were used to construct a competing endogenous RNA (ceRNA) network. Pulmonary artery endothelial cells were transfected with modified lncRNA-92467 or miR-205-5p to assess their regulatory functions. Finally, mice were injected with AAV-Control or AAV-PTPRM shRNA (2.5 × 10¹¹ v.g./mL per mouse). Hemodynamic and echocardiographic analyses were performed to evaluate the in vivo role of PTPRM.

We identified that lncRNA-92467 functions as a competing endogenous RNA (ceRNA) by competitively binding to miR-205-5p, thereby upregulating its target gene PTPRM. Knockdown of lncRNA-92467 significantly promoted pulmonary artery endothelial cell proliferation and migration. These effects were abolished by a miR-205-5p inhibitor, which also restored PTPRM expression. Functional assays confirmed that miR-205-5p enhanced cell proliferation and migration while inhibiting apoptosis; these effects were reversed by PTPRM overexpression. In vivo, exogenous PTPRM overexpression attenuated HPH progression in mice. Mechanistically, PTPRM directly targeted cell adhesion molecules (CAMs), which increased catenin production, thereby inhibiting abnormal cell proliferation and migration and promoting apoptosis.

Our findings reveal a novel lncRNA-92467/miR-205-5p/PTPRM/CAMs regulatory axis in HPH pathogenesis. These results suggest that PTPRM may serve as a promising therapeutic target for HPH.