To study the effects of ABT-737 on rats with hypoxic pulmonary hypertension (PAH), and investigate the underlying mechanism from the aspect of NIX-mediated mitophagy.

According to random number table, 18 SD rats were randomly divided into 3 groups (n=6 each): control group, hypoxic group (including 1 death) and treatment group. The rats in hypoxic group and treatment group were treated with hypoxia for 8 h/day, totally 4 weeks. The treatment group was given intraperitoneal administration of ABT-737 15 mg/(kg·day) before hypoxic rearing, while other groups received the same volume of vehicle. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVHI), and pulmonary artery morphological features as well as wall thickness index (WTI) were assessed 4 weeks later. The expression of NIX, microtubule-associated protein 1 light chain 3 (LC3)-Ⅱ/LC3-Ⅰ and translocase of the outer membrane (Tom)20 protein was detected by Western blotting.

RVSP in control group, hypoxic group and treatment group was (15.76±1.27), (43.16±4.34) and (29.77±2.21) mmHg respectively. RVHI in control group, hypoxic group and treatment group was 0.28±0.04, 0.37±0.02 and 0.29±0.03 respectively. WTI in control group, hypoxic group and treatment group was (6.51±2.46)%, (14.60±2.33)% and (10.20±3.24)% respectively. As compared with those in control group, RVSP, RVHI and WTI in hypoxic group were significantly increased (P=0.000, 0.002 and 0.000 respectively). Rats in treatment group showed significantly lower RVSP, RVHI and WTI than in hypoxic group (P values were 0.000), but RVSP and WTI in treatment group were still increased as compared with those in control group (P values were 0.000). The expression of NIX in hypoxic group (0.93±0.11) was up-regulated as compared with control group (0.60±0.13, P=0.001), and that in treatment group (1.25±0.12) was even significantly higher (P=0.000). LC3-Ⅱ/LC3-Ⅰ ratio in treatment group (1.59±0.53) was significantly higher than in control group (0.71±0.32, P=0.006) and hypoxic group (0.94±0.20, P=0.032). The expression of Tom20 in hypoxic group (1.20±0.23) was remarkably increased as compared with that in control group (0.84±0.15, P=0.009). This increase was suppressed by the ABT-737 intervention (0.97±0.08, P=0.040).

Hypoxia induces PAH and pulmonary vascular remodeling and increases the expression of Tom20 in rats. ABT-737 can alleviate hypoxia-induced PAH by promoting the NIX-mediated mitophagy, which can help Tom20 to be degraded.

ABT-737; NIX; Mitophagy; Hypoxia; Pulmonary artery hypertension