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Inhibition of YAP1 Via Verteporfin Attenuates Hypoxia- or Hypoxia Sugen Mediated Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rodents
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A3740 - Inhibition of YAP1 Via Verteporfin Attenuates Hypoxia- or Hypoxia Sugen Mediated Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rodents
Author Block: J. Chen1, S. Zhao1, Y. Wang1, N. Felesena1, L. Huang2, R. F. Machado3; 1Dept of Medicine, Univ of Illinois at Chicago, Chicago, IL, United States, 2Pharmacology, University of Illinois at Chicago, Chicago, IL, United States, 3Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University, Indianapolis, IN, United States.
Rationale: YAP1, an important oncogene, regulates cell proliferation. In this study, we investigated whether inhibiting YAP1 via verteporfin can block experimental models of pulmonary hypertension (PH) and pulmonary vascular remodeling. Methods: A mouse model of hypoxia-mediated PH (HPH) and a rat model of hypoxia plus Sugen (HSU) mediated severe PH were used in this study. Eight week old C57Bl6 male mice were exposed to normoxia or 10% FiO2 for four weeks (n=10 per group). At the Day 14, mice were treated with verteporfin (4.5 mg/kg bw, IP, every other day) for two weeks. In the rats, one dose of Sugen (20 mg/kg bw, IQ) was delivered to the 200 g rats that were then exposed to normoxia or 10% FiO2 for three weeks (n=6 per group). The rats were reoxygenated for two weeks, and then treated with verteporfin (25 mg/kg bw, IP, every other day) for two weeks. Right ventricular systolic pressure (RVSP) was determined with a Millar pressure transducer catheter. The right ventricle: left ventricle + septum (RV/LV+S) ratio was calculated to assess right ventricular hypertrophy (RVH). Pulmonary artery remodeling was assessed using Aperio image software to measure the ratio of pulmonary vessel wall area to total vessel area. Results: Under normoxic or normoxia + sugen exposure, RVSP and RVH did not differ between verteporfin-treated and vehicle groups. In mouse HPH model, verteporfin significantly attenuated hypoxia induced RVSP (35.63 ± 0.84 vs 31.28 ± 0.57, p=0.0086) and RVH (0.39 ± 0.013 vs 0.34 ± 0.013, p=0.044). Similar findings occurred in HSU mediated severe PH in rats (RVSP: 78.07 ± 3.83 vs 57.90 ± 5.64, p=0.012; RVH: 0.63 ± 0.014 vs 0.52 ± 0.017, p=0.0008). In both models, the degree of pulmonary vascular remodeling assessed by the ratio of pulmonary vessel wall area to total vessel area was significantly attenuated by verteporfin. Conclusion: YAP1 inhibition via Verteporfin attenuates experimental PH and pulmonary vascular remodeling. Verteporfin may have a therapeutic effect on pulmonary hypertension.
Author Block: J. Chen1, S. Zhao1, Y. Wang1, N. Felesena1, L. Huang2, R. F. Machado3; 1Dept of Medicine, Univ of Illinois at Chicago, Chicago, IL, United States, 2Pharmacology, University of Illinois at Chicago, Chicago, IL, United States, 3Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University, Indianapolis, IN, United States.
Rationale: YAP1, an important oncogene, regulates cell proliferation. In this study, we investigated whether inhibiting YAP1 via verteporfin can block experimental models of pulmonary hypertension (PH) and pulmonary vascular remodeling. Methods: A mouse model of hypoxia-mediated PH (HPH) and a rat model of hypoxia plus Sugen (HSU) mediated severe PH were used in this study. Eight week old C57Bl6 male mice were exposed to normoxia or 10% FiO2 for four weeks (n=10 per group). At the Day 14, mice were treated with verteporfin (4.5 mg/kg bw, IP, every other day) for two weeks. In the rats, one dose of Sugen (20 mg/kg bw, IQ) was delivered to the 200 g rats that were then exposed to normoxia or 10% FiO2 for three weeks (n=6 per group). The rats were reoxygenated for two weeks, and then treated with verteporfin (25 mg/kg bw, IP, every other day) for two weeks. Right ventricular systolic pressure (RVSP) was determined with a Millar pressure transducer catheter. The right ventricle: left ventricle + septum (RV/LV+S) ratio was calculated to assess right ventricular hypertrophy (RVH). Pulmonary artery remodeling was assessed using Aperio image software to measure the ratio of pulmonary vessel wall area to total vessel area. Results: Under normoxic or normoxia + sugen exposure, RVSP and RVH did not differ between verteporfin-treated and vehicle groups. In mouse HPH model, verteporfin significantly attenuated hypoxia induced RVSP (35.63 ± 0.84 vs 31.28 ± 0.57, p=0.0086) and RVH (0.39 ± 0.013 vs 0.34 ± 0.013, p=0.044). Similar findings occurred in HSU mediated severe PH in rats (RVSP: 78.07 ± 3.83 vs 57.90 ± 5.64, p=0.012; RVH: 0.63 ± 0.014 vs 0.52 ± 0.017, p=0.0008). In both models, the degree of pulmonary vascular remodeling assessed by the ratio of pulmonary vessel wall area to total vessel area was significantly attenuated by verteporfin. Conclusion: YAP1 inhibition via Verteporfin attenuates experimental PH and pulmonary vascular remodeling. Verteporfin may have a therapeutic effect on pulmonary hypertension.
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