Apigenin Attenuates Pulmonary Hypertension by Inducing PASMCs Mitochondria-Dependent Apoptosis Via Inhibiting Hypoxia Inducible Factor 1α-KV1.5 Channel Pathway

Abstract

Background: To assess the therapeutic effect of apigenin on pulmonary hypertension (PH) and explore the underlying mechanisms of apigenin in PASMCs proliferation and apoptosis. Methods: Hypoxic PH model was established in Sprague-Dawley rats and administration with apigenin. RV systolic pressure (RVSP), RV weight (RV/LV+S) %, mean systolic blood pressure were measured and pulmonary vascular remolding calculated. PASMCs apoptosis and proliferation were respectively detected by TUNEL and PCNA immunohistochemistry. Immunoblot analysis, mitochondrial membrane potential (Δψm) were detected in vivo and in vitro. Also, KV1.5 inhibitor diphenyl phosphine oxide-1(DPO-1) and HIF-1α overexpression lentiviral vector were used to search functional studies. Findings: Administration of apigenin prevented the development of PH, hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling, and also prevented progression of established PH. Meanwhile, apigenin exhibits an inducing effects of mitochondria-dependent apoptosis on hypoxic PASMCs. In addition, apigenin could reverse the KV1.5 expression which inhibited by hypoxia both in vivo and in vitro. However, KV1.5 inhibitor, diphenyl phosphine oxide-1(DPO-1), can offset apigenin-induced mitochondria-dependent apoptosis. Moreover, functional studies revealed that apigenin activated mitochondria-dependent apoptosis by modulation of hypoxia-induced factor 1α (HIF-1α) signaling. Interpretation: Our studies revealed that apigenin attenuates PH via inhibiting HIF-1α-KV1.5 channel pathway to induce PASMCs mitochondria-dependent apoptosis. Funding: The National Natural Science Foundation of China (No. 81700051, 81670048, and 81700052), the National Key Technology R&D Program of the 12th National Five-year Development Plan (No. 2012BAI05B01), and the National Key Research and Development Pro-grams of China (No. 2016YFC1304500, 2016-YFC0903600). Declaration of Interest: The authors declare that they have no conflicts of interest concerning this article. Ethical Approval: All of the rats studies were approved by the Huazhong University of Science and Technology Committee and the Tongji Medical College Ethics Committee at Tongji Hospital and were performed to conform to NIH guidelines (Guide for the Care and Use of Laboratory Animals).