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Cathepsin S Signaling Promotes Pulmonary Vascular Remodeling
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A3751 - Cathepsin S Signaling Promotes Pulmonary Vascular Remodeling
Author Block: Y. Lai1, C. Chang2; 1Respiratory Therapy, Chang Gung University, Tao-Yuan, Taiwan, 2Cardiovascular Division, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
RATIONALE: Cysteine cathepsin proteases play significant roles in the development of cardiovascular diseases and are associated with extracellular matrix (ECM) degradation. Patients with pulmonary arterial hypertension (PAH) reveal increased proteases by pulmonary arterial smooth muscle cells (PASMCs), which is related to the degradation of elastic fibers and pulmonary vascular remodeling. However, the mechanism by which cathepsin proteases regulate the ECM degradation and PASMC proliferation in PAH remains unclear. We hypothesized that cathepsin proteases in PASMCs promote the PAH remodeling.
METHODS and RESULTS: Here, we confirm that cathepsin S (CatS) overexpression and degradation of elastic laminae in the pulmonary artery media layer of idiopathic PAH patients and in the PASMCs of MCT-induced PAH model rats. In addition, pulmonary hypertension can be treated in MCT-PAH rats by administration of a selective CatS inhibitor which stimulates peroxisome proliferator-activated receptor-gamma (PPARγ) to inhibit the expression of CatS, thus suppressing the proliferation and migration of MCT-PAH PASMCs. We then reduced CatS or PPARγ by small interfering RNA in human PASMCs to demonstrate a mechanistic link between CatS signaling and PPARγ protein, and the results suggested that PPARγ is upstream of CatS signaling. The defective CatS induced by siRNA caused increased elastin and P21 and, in addition, decreased Notch3 and Hairy/Enhancer of Split-5 (Hes5) proteins, which are important for the development of PAH.
CONCLUSIONS: The activity of smooth muscle CatS in pulmonary vascular remodeling and degradation of elastin fibers through disruption of PPARγ is of pathophysiological significance in PAH.
Author Block: Y. Lai1, C. Chang2; 1Respiratory Therapy, Chang Gung University, Tao-Yuan, Taiwan, 2Cardiovascular Division, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
RATIONALE: Cysteine cathepsin proteases play significant roles in the development of cardiovascular diseases and are associated with extracellular matrix (ECM) degradation. Patients with pulmonary arterial hypertension (PAH) reveal increased proteases by pulmonary arterial smooth muscle cells (PASMCs), which is related to the degradation of elastic fibers and pulmonary vascular remodeling. However, the mechanism by which cathepsin proteases regulate the ECM degradation and PASMC proliferation in PAH remains unclear. We hypothesized that cathepsin proteases in PASMCs promote the PAH remodeling.
METHODS and RESULTS: Here, we confirm that cathepsin S (CatS) overexpression and degradation of elastic laminae in the pulmonary artery media layer of idiopathic PAH patients and in the PASMCs of MCT-induced PAH model rats. In addition, pulmonary hypertension can be treated in MCT-PAH rats by administration of a selective CatS inhibitor which stimulates peroxisome proliferator-activated receptor-gamma (PPARγ) to inhibit the expression of CatS, thus suppressing the proliferation and migration of MCT-PAH PASMCs. We then reduced CatS or PPARγ by small interfering RNA in human PASMCs to demonstrate a mechanistic link between CatS signaling and PPARγ protein, and the results suggested that PPARγ is upstream of CatS signaling. The defective CatS induced by siRNA caused increased elastin and P21 and, in addition, decreased Notch3 and Hairy/Enhancer of Split-5 (Hes5) proteins, which are important for the development of PAH.
CONCLUSIONS: The activity of smooth muscle CatS in pulmonary vascular remodeling and degradation of elastin fibers through disruption of PPARγ is of pathophysiological significance in PAH.
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