Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs.

Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca(2+) concentration ([Ca(2+)]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca(2+)]i increases in hypoxic PASMCs. The level of BMP4 mature protein was increased for ∼183% in distal pulmonary arterial smooth muscle (PA) from CH (10% O2 for 21 days; CH) exposed rats, and 143% in PASMCs cultured under prolonged hypoxia (4% O2 for 60 h). In rat PASMCs, HIF-1α overexpression up-regulated, whereas HIF-1α knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca(2+)]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for ∼80%, which was absent in HIF-1α heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca(2+)]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1α knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1α or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca(2+)]i. BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca(2+)]i in PASMCs, promoting CHPH pathogenesis.

Wang J ，Fu X ，Yang K ，Jiang Q ，Chen Y ，Jia J ，Duan X ，Wang EW ，He J ，Ran P ，Zhong N ，Semenza GL ，Lu W ... -  《-》

BMP4 increases canonical transient receptor potential protein expression by activating p38 MAPK and ERK1/2 signaling pathways in pulmonary arterial smooth muscle cells.

Li X ，Lu W ，Fu X ，Zhang Y ，Yang K ，Zhong N ，Ran P ，Wang J ... -  《-》

Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells.

Wang J ，Weigand L ，Lu W ，Sylvester JT ，Semenza GL ，Shimoda LA ... -  《-》

Chrysin Alleviates Chronic Hypoxia-Induced Pulmonary Hypertension by Reducing Intracellular Calcium Concentration in Pulmonary Arterial Smooth Muscle Cells.

Dong F ，Zhang J ，Zhu S ，Lan T ，Yang J ，Li L ... -  《-》

Chronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2+ channels in pulmonary arterial smooth muscle cells: a novel mechanism of hypoxic pulmonary hypertension.

Lin MJ ，Leung GP ，Zhang WM ，Yang XR ，Yip KP ，Tse CM ，Sham JS ... -  《-》