RESUMO
Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3-/-) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH.
Assuntos
Hipertensão Pulmonar , Animais , Humanos , Camundongos , Ratos , Proliferação de Células , Células Cultivadas , Células Endoteliais/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Artéria Pulmonar/metabolismo , Remodelação Vascular/genéticaRESUMO
Background: High-altitude pulmonary hypertension (HAPH) is a common disease in regions of high altitude where performing right heart catheterization (RHC) is challenging. The development of a diagnostic scoring system is crucial for effective disease screening. Methods: A total of 148 individuals were included in a retrospective analysis, and an additional 42 residents were prospectively enrolled. We conducted a multivariable analysis to identify independent predictors of HAPH. Subsequently, we devised a prediction score based on the retrospective training set to anticipate the occurrence and severity of HAPH. This scoring system was further subjected to validation in the prospective cohort, in which all participants underwent RHC. Results: This scoring system, referred to as the GENTH score model (Glycated hemoglobin [OR = 4.5], Echocardiography sign [OR = 9.1], New York Heart Association-functional class [OR = 12.5], Total bilirubin [OR = 3.3], and Hematocrit [OR = 3.6]), incorporated five independent risk factors and demonstrated strong predictive accuracy. In the training set, the area under the curve (AUC) values for predicting the occurrence and severity of HAPH were 0.851 and 0.832, respectively, while in the validation set, they were 0.841 and 0.893. In the validation set, GENTH score model cutoff values of ≤18 or >18 points were established for excluding or confirming HAPH, and a threshold of >30 points indicated severe HAPH. Conclusions: The GENTH score model, combining laboratory and echocardiography indicators, represents an effective tool for distinguishing potential HAPH patients and identifying those with severe HAPH. This scoring system improves the clinical screening of HAPH diseases and offers valuable insights into disease diagnosis and management.