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

BACKGROUND: Pulmonary hypertension (PH) is a fatal progressive disease characterized by pulmonary endothelial injury and occlusive pulmonary vascular remodeling. Lysosomal protease cathepsin L degrades essential molecules to participate in the human pathophysiological process. BMPR2 (bone morphogenetic protein type II receptor) deficiency, an important cause of PH, results from mutational inactivation or excessive lysosomal degradation and induces caspase-3-mediated cell death. Given recent evidence that pyroptosis, as a new form of programmed cell death, is induced by caspase-3-dependent GSDME (gasdermin E) cleavage, we hypothesized that cathepsin L might promote PH through BMPR2/caspase-3/GSDME axis-mediated pyroptosis. METHODS: Cathepsin L expression was evaluated in the lungs and plasma of patients with pulmonary arterial hypertension. The role of cathepsin L in the progression of PH and vascular remodeling was assessed in vivo. Small interfering RNA, specific inhibitors, and lentiviruses were used to explore the mechanisms of cathepsin L on human pulmonary arterial endothelial cell dysfunction. RESULTS: Cathepsin L expression is elevated in pulmonary artery endothelium from patients with idiopathic pulmonary arterial hypertension and experimental PH models. Genetic ablation of cathepsin L in PH rats relieved right ventricular systolic pressure, pulmonary vascular remodeling, and right ventricular hypertrophy, also restoring endothelial integrity. Mechanistically, cathepsin L promotes caspase-3/GSDME-mediated endothelial cell pyroptosis and represses BMPR2 signaling activity. Cathepsin L degrades BMPR2 via the lysosomal pathway, and restoring BMPR2 signaling prevents the pro-pyroptotic role of cathepsin L in PAECs and experimental PH models. CONCLUSIONS: These results show for the first time that cathepsin L promotes the development of PH by degrading BMPR2 to induce caspase-3/GSDME-mediated endothelial pyroptosis.

  • Peng, Z.
  • Luo, X. Y.
  • Li, X.
  • Li, Y.
  • Wu, Y.
  • Tian, Y.
  • Pan, B.
  • Petrovic, A.
  • Kosanovic, D.
  • Schermuly, R. T.
  • Ruppert, C.
  • Günther, A.
  • Zhang, Z.
  • Qiu, C.
  • Li, Y.
  • Pu, J.
  • Li, X.
  • Chen, A. F.

Keywords

  • bone morphogenetic proteins
  • caspase 3
  • cathepsin L
  • gasdermins
  • pulmonary arterial hypertension
  • pyroptosis
Publication details
DOI: 10.1161/hypertensionaha.124.22903
Journal: Hypertension
Work Type: Original
Access number: 39403807
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