ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2022; 18(6):2372-2391. doi:10.7150/ijbs.70247 This issue Cite
Research Paper
Compensatory roles of Protein Related to DAN and Cerberus (PRDC) decrease in pulmonary arterial hypertension
1. Department of Anesthesiology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China.
2. Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
3. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
4. Department of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
5. Department of neurosurgery, Shenzhen University General Hospital, Shenzhen 518055, China.
6. Department of neurosurgery, Shenzhen University Clinical Medical Academy, Shenzhen 518055, China.
7. Department of Organ Transplantation and Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
#These authors contributed equally to this work.
Abstract
Bone morphogenetic protein (BMP) signaling is commonly suppressed in patients with pulmonary arterial hypertension (PAH), but the compensatory mechanism of BMP signaling suppression is incompletely elucidated. This study aimed to investigate the role of PRDC, an antagonist of BMPs, in PAH and the underlying mechanism. Human lungs were collected and rat PAH was induced (monocrotaline, 60 mg/kg). BMP cascade and PRDC were detected in lungs and distal pulmonary artery smooth muscle cells (dPASMCs). In vitro cell experiments and in vivo supplementation of PRDC in hypertensive rats were subsequently performed. PRDC and BMP cascade all decreased in human and rat hypertensive lungs. Cell experiments confirmed that BMP2/4 inhibited dPASMCs proliferation by increasing cell cycle inhibitors (p21, p27), prevented dPASMCs migration by down-regulating MMP2/9 and up-regulating TIMP1/2 expression, and promoted dPASMCs apoptosis by up-regulating Bax, caspase3/9 and down-regulating Bcl-2 expression, as well as enhancing caspase3/7 activity, while, PRDC reversed the effects of BMP2/4 on dPASMCs proliferation, migration and apoptosis. In vivo trial found that PRDC supplementation deteriorated rat PAH in terms of pulmonary hemodynamics, vasculopathies and right ventricle hypertrophy. Taken together, compensatory decrease of PRDC in hypertensive lungs theoretically slow down the natural course of PAH, suggesting its therapeutic potential in PAH.
Keywords: Pulmonary arterial hypertension, pulmonary vascular remodeling, bone morphogenetic protein, monocrotaline, PRDC
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