| First Author | Wang J | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 107 |
| Issue | 1 | Pages | 108-18 |
| PubMed ID | 25824146 | Mgi Jnum | J:257129 |
| Mgi Id | MGI:6106164 | Doi | 10.1093/cvr/cvv122 |
| Citation | Wang J, et al. (2015) Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs. Cardiovasc Res 107(1):108-18 |
| abstractText | AIMS: 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. METHODS AND RESULTS: The level of BMP4 mature protein was increased for approximately 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-1alpha overexpression up-regulated, whereas HIF-1alpha 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 approximately 80%, which was absent in HIF-1alpha 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-1alpha knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1alpha or BMP4 abolished hypoxia-induced TRPC expression and basal [Ca(2+)]i. CONCLUSIONS: 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. |
