Apigenin attenuates pulmonary hypertension by inducing mitochondria-dependent apoptosis of PASMCs via inhibiting the hypoxia inducible factor 1α–KV1.5 channel pathway. (1st February 2020)

• Record Type: Journal Article
• Authors: He, Yuanzhou; Fang, Xiaoyu; Shi, Jing; Li, Xiaochen; Xie, Min; Liu, Xiansheng
• Is Part Of: Chemico-biological interactions. Volume 317(2020)
• Publication Date: 2020-02-01
• Subjects: Apigenin -- Pulmonary hypertension -- HIF-1α -- KV1.5 -- Apoptosis; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2020.108942
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Pulmonary hypertension (PH) is distal pulmonary arterial remodelling and is mainly due to the abnormal proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Apigenin, a natural dietary flavonoid, is a promising PH preventive agent that inhibits PASMC proliferation and induces apoptosis. In this study, we investigated the biological effects of apigenin on PH. PH was induced in male Sprague-Dawley rats by chronic hypoxia exposure. Administration of apigenin prevented the development of PH, hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodelling and prevented the progression of established PH in this model. Moreover, treatment with apigenin induced mitochondria-dependent apoptosis. To explore the underlying mechanisms, the mitochondrial membrane potential (Δψm) and the mitochondria-dependent apoptosis factors cytochrome C, BAX, Bcl-2, cleaved caspase 3, and cleaved caspase 9 were analysed. These results confirmed that apigenin induces mitochondria-dependent apoptosis in hypoxic PASMCs to protect against PH. In addition, treatment with apigenin reversed hypoxia-induced inhibition of KV1.5 expression both in vivo and in vitro . The KV1.5 inhibitor diphenyl phosphine oxide-1 (DPO-1) abrogated apigenin-induced mitochondria-dependent apoptosis in hypoxic PASMCs, suggesting that KV1.5 is implicated in apigenin-induced mitochondria-dependent apoptosis. Furthermore, functional studies revealed that apigenin activated mitochondria-dependent apoptosis by modulation of hypoxia-induced factor 1α (HIF-1α) signalling. Together, our study shows that apigenin attenuates PH via inhibiting the HIF-1α-KV1.5 channel pathway to induce PASMC mitochondria-dependent apoptosis. Highlights: Apigenin ameliorate hypoxia-induced PAH and pulmonary arterial remodelling. Apigenin induced mitochondria-dependent apoptosis. Apigenin attenuates PH via inhibiting the HIF-1α-KV1.5 channel pathway.