Cathepsin L Promotes Pulmonary Hypertension via BMPR2/GSDME-Mediated Pyroptosis

Area of Science:

• Cardiovascular Research
• Cell Biology
• Molecular Medicine

Background:

• Pulmonary hypertension (PH) is a severe disease involving lung vascular remodeling and endothelial injury.
• Lysosomal protease cathepsin L plays a role in cellular processes, and its dysregulation is implicated in PH.
• Bone morphogenetic protein type II receptor (BMPR2) deficiency is a known cause of PH, linked to cell death pathways.

Purpose of the Study:

• To investigate the role of cathepsin L in PH pathogenesis.
• To explore the potential link between cathepsin L, BMPR2, and pyroptosis in PH.
• To determine if targeting cathepsin L could be a therapeutic strategy for PH.

Main Methods:

• Assessed cathepsin L expression in human PH samples and animal models.
• Utilized in vivo models to evaluate cathepsin L's impact on PH progression and vascular remodeling.
• Employed molecular techniques (siRNA, inhibitors, lentiviruses) to study cathepsin L's mechanism in pulmonary arterial endothelial cells.

Main Results:

• Elevated cathepsin L expression was observed in PH patients and models.
• Genetic removal of cathepsin L improved PH indicators in rats, including reduced vascular remodeling and restored endothelial integrity.
• Cathepsin L was found to induce pyroptosis by degrading BMPR2, thereby inhibiting BMPR2 signaling.

Conclusions:

• Cathepsin L drives PH development by degrading BMPR2, which triggers caspase-3/gasdermin E (GSDME)-mediated endothelial pyroptosis.
• Restoring BMPR2 signaling can counteract the pro-pyroptotic effects of cathepsin L.
• These findings highlight cathepsin L as a key mediator in PH and a potential therapeutic target.