Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

Abstract

Numerous studies have demonstrated that altered expression levels of four and a half LIM domains 1 (FHL1) and P21 are necessary for hypoxia-induced pulmonary vascular remodeling in both adult rats and human patients with idiopathic pulmonary arterial hypertension. However, whether FHL1 and P21 are present in the pulmonary artery and whether these proteins affect pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH) in neonatal rats remain unknown. The present study investigated the effects of altered FHL1 and P21 expression on pulmonary vascular remodeling in neonatal rats with HPH. A total of 32 newborn Sprague-Dawley rats were exposed to hypoxia or room air for 7 or 14 days (n=8/subgroup). Parameters including the percentage of medial wall thickness (WT%), the percentage of medial wall area (WA%), right ventricular (RV) mean pressure, RV hypertrophy index (RVHI) and RV systolic pressure (RVSP) were measured to evaluate the development of HPH. Additionally, the expressions of FHL1 and P21 in the pulmonary artery smooth muscle cells (PASMCs) were measured by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemical staining. WA%, WT%, RV mean pressure, RVHI and RVSP were significantly increased in the HPH model group when compared with the control group (P<0.01). The protein expression levels of FHL1 were significantly increased in the HPH group (P<0.05), while the mRNA and protein expression levels of P21 were significantly reduced (P<0.05). Pearson correlation analysis indicated that the protein expressions of FHL1 and P21 were correlated with WA% and WT% (all P<0.001), and that the protein expression of P21 was negatively correlated with that of FHL1 (P<0.01). The results indicated that the expressions of FHL1 and P21 were altered in the PASMCs of newborn rats with HPH. Furthermore, FHL1 and P21 may serve important roles in pulmonary vascular remodeling.

Sildenafil protects against pulmonary hypertension induced by hypoxia in neonatal rats via activation of PPARγ‑mediated downregulation of TRPC

“…Model preparation. According to our previously established method (21,22), newborn rats were fed by maternal rats after full-term delivery and maintained under normal atmospheric conditions for 48 h. In the pre-experiment, 15 neonatal rats were randomly divided into 5 groups according to their body weight: i) Normoxic control group [fraction of inspired oxygen (FiO 2 ) 0.21±0.05; temperature 25-27˚C; humidity 50-70%; n=3]; ii) hypoxia group (FiO 2 0.1±0.05; temperature 25-27˚C; humidity 50-70%; n=3); iii) hypoxia + 5 mg/kg/day sildenafil group (FiO 2 0.1±0.05; temperature 25-27˚C; humidity 50-70%; sildenafil 5 mg/kg/day; n= 3); iv) hypoxia + 10 mg/kg/day sildenafil group (FiO 2 0.1±0.05; temperature 25-27˚C; humidity 50-70%; sildenafil 10 mg/kg/day; n=3); and v) hypoxia + 25 mg/kg/day sildenafil group (FiO 2 0.1±0.05; temperature 25-27˚C; humidity 50-70%; sildenafil 25 mg/kg/day; n=3). The oxygen concentration and air humidity were continuously monitored.…”