Hypoxia Upregulation of BACH1 Aggravates Pulmonary Hypertension Through TGFBR2/SMAD Pathways

BACKGROUND: Vascular remodeling is a central characteristic of pulmonary hypertension (PH), yet the precise mechanisms underlying this process remain poorly understood. METHODS: The coimmunoprecipitation assay was used to explore prolyl hydroxylase that modifies BACH1 (BTB and CNC homology 1). Cultured pulmonary artery smooth muscle cells, rodent models with PH, specimens from patients with idiopathic pulmonary arterial hypertension, and single-nucleus RNA sequencing were used to study the role of BACH1 in the regulation of PH and the underlying mechanisms. RESULTS: In this study, we found that the transcription factor BACH1 was upregulated in lung tissues and pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension and animals with experimental PH. Under normoxia, the prolyl hydroxylation of BACH1, mediated by PHD (prolyl hydroxylase) 2, facilitated BACH1 degradation by VHL (von Hippel-Lindau) protein. Hypoxic exposure decreased this prolyl hydroxylation with subsequent increased BACH1 protein stability. The deficiency or overexpression of BACH1 in smooth muscle cells in mice alleviated or exacerbated pulmonary vascular remodeling and hypoxia-induced PH. Hypoxia triggered the accumulation of BACH1 and its recruitment to the promoter region of TGFBR2 (transforming growth factor β receptor type II) in smooth muscle cells. This recrui tment activated TGFBR2 transcription, thereby promoting vascular remodeling by upregulating SMAD (suppressor of mothers against decapentaplegic) signaling and extracellular matrix deposition. Decreased TGFBR2 expression or inhibited kinase activity significantly attenuated the BACH1-induced extracellular matrix genes. Furthermore, the BACH1-enhanced PH development was blunted by a TGFBR2 kinase inhibitor. CONCLUSIONS: Our study illustrates that BACH1 is prolyl-hydroxylated in an oxygen/PHD-dependent manner, affecting its stability through VHL. BACH1 is crucial for hypoxia-induced PH by activating TGFBR2/SMAD in smooth muscle cells. Thus, BACH1 inhibition may be a potential therapeutic strategy for PH.