新型p38丝裂原活化蛋白激酶抑制剂可逆转大鼠缺氧诱导的肺动脉高压
Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.
作者信息
Silva Grazielle Fernandes, da Silva Jaqueline Soares, de Alencar Allan Kardec Nogueira, de Moraes Carvalho da Silva Marina, Montagnoli Tadeu Lima, de Souza Rocha Bruna, de Freitas Rosana Helena Coimbra Nogueira, Sudo Roberto Takashi, Fraga Carlos Alberto Manssour, Zapata-Sudo Gisele
机构信息
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
Programa de Pós-Graduação em Cardiologia, Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil.
出版信息
Pharmaceuticals (Basel). 2022 Jul 21;15(7):900. doi: 10.3390/ph15070900.
Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.
丝裂原活化蛋白激酶（MAPK）信号通路与肺动脉高压（PH）和右心室（RV）衰竭中的心血管重塑密切相关。研究了一种新设计的p38抑制剂LASSBio-1824在实验性诱导的PH中的作用。将雄性Wistar大鼠暴露于低氧环境和SU5416（SuHx），以常氧大鼠作为对照。用赋形剂或LASSBio-1824（50 mg/kg）进行为期14天的口服治疗。通过超声心动图和导管插入术评估肺血管阻力以及RV的结构和功能。对肺和RV进行组织学、免疫组织化学和蛋白质印迹分析，以研究心血管重塑和炎症。LASSBio-1824治疗通过减轻血管肌化和内皮功能障碍使血管阻力恢复正常。在心脏方面，治疗降低了RV收缩压、减轻了肥厚并减少了胶原蛋白含量，改善了心脏功能。治疗后，肺血管和RV组织中TNF-α、iNOS、磷酸化p38和caspase-3的蛋白质含量均降低，并且在接受治疗的SuHx大鼠的心肌细胞中发现转录因子c-fos的激活减少。因此，LASSBio-1824是针对PH进行重塑靶向治疗的潜在候选药物。
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