TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension.

BACKGROUND Pulmonary arterial hypertension (PAH) is a refractory disease. Its prognosis remains poor; hence, establishment of novel therapeutic targets is urgent. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53, and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). Recently, p53 was shown to suppress the PAH progression. Since inhibition of autophagy and ROS are known to improve PAH, we examined the effect of TIGAR on PAH progression. METHODS We compared pulmonary hypertension (PH) development between TIGAR-deficient knockout (KO) and wild type (WT) mice using a hypoxia-induced PH model. Human pulmonary artery smooth muscle cells (PASMCs) were used for in vitro experiments with small interfering RNA (siRNA) to investigate the possible molecular mechanisms. RESULTS From analysis of right ventricular pressure, right heart weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in the WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation was increased in TIGAR KO mice. Autophagy and ROS activity was also increased in TIGAR KO mice. TIGAR knockdown by siRNA increased cell proliferation and migration, exacerbated autophagy, and increased ROS generation during hypoxia. Autophagy inhibition by chloroquine and ROS inhibition by N-acetylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. CONCLUSIONS TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS, and therefore, improved hypoxia-induced PH. Thus, TIGAR might be a promising therapeutic target for PAH.