The role of ATG-7 contributes to pulmonary hypertension by impacting vascular remodeling.

AIM Pulmonary hypertension (PH) is a pathophysiological syndrome with functional abnormalities of the pulmonary artery and heart, eventually becoming life threatening to the patients. Autophagy-related gene 7 (ATG)-7 is involved in many cardiovascular diseases, but little is known about the specific role of ATG-7 in the development of PH. We aimed to examine the expression of ATG-7 in PH patients and PH mice, specifically investigate pulmonary physiological responses in a mouse model with conditional deletion of ATG-7 in smooth muscle cells (SMCs) and further clarify the mechanism of PH caused by ATG-7 deficiency. METHODS AND RESULTS SMC-ATG-7-/- mice underwent echocardiography and subsequent pulmonary arterial pressure (PAP) checks. The PAP was lower in wild-type (WT) mice (22.6 ± 2.0 mmHg) than knockout (KO) mice (34.0 ± 2.5 mmHg; P < 0.001). Pulmonary artery resistance was increased in KO (17.61 ± 2.03 mm2·s-1) versus WT mice (8.91 ± 1.62 mm2·s-1; P < 0.005). Combined with these statistics, SMC-ATG7-/- mice were diagnosed with PH. The increase of ATG-7 expression in vessels from PH patients and PH mice were assessed and the effects of ATG-7 on vascular remodeling were investigated in SMCs using relevant methods. We also identified silencing ATG-7 in SMCs induced the increased level of Ca2+ and abnormal proliferation through PP2A/ 4EBP-1/ elf-4E pathway. CONCLUSIONS ATG-7 affects vascular remodeling and exerts a protective function during the pathogenesis of PH. Our study revealed a novel mechanism ATG-7 deficiency promotes cell proliferation via the interaction between PP2A, 4EBP1 and elf-4E.