Key result
HIMF induces pulmonary hypertension by directly binding to the BMPR1A ectodomain and disrupting BMPR2 activity, a process that can be attenuated by a targeted blocking peptide.
HIMF induces pulmonary hypertension by binding to BMPR1A and disrupting BMPR2 signaling, identifying a novel therapeutic target for pulmonary hypertension.
BACKGROUND: HIMF (hypoxia-induced mitogenic factor) induces pulmonary hypertension; however, the molecular nature of its extracellular membrane receptor(s) remains unknown. METHODS: A combination of cross-immunoprecipitation and immunoblotting, yeast 2-hybrid assays, and proteomics analysis was performed to screen and identify the candidate receptors. The interaction of HIMF with these candidate(s) was further evaluated using overexpression, silencing, point mutation, and blocking peptide strategies in chronic hypoxia and sugen/hypoxia pulmonary hypertension rat models to decipher the underlying pathophysiologic mechanisms. RESULTS: Cross-immunoprecipitation and immunoblotting identified HIMF interaction with the BMPR2 (bone morphogenetic protein receptor 2) complex. Yeast 2-hybrid revealed HIMF binding to the DTLPF motif (Asp-Thr-leucine-Pro-Phe) at the 54 to 58 amino acids (aa) in the extracellular domain of the BMPR1A (bone morphogenetic protein receptor 1A), one partner of the BMPR2 heterodimeric complex, but not BMPR2 itself. HIMF and human counterpart RELM (resistin-like molecule)-β binding to BMPR1A disrupted the BMPR1A/BMPR2 complex and decreased BMPR2 activity as revealed by reduced downstream events including ≈43% to 56% decline in Smad/1/5/9 phosphorylation and ≈41% to 60% decrease in Id-1 expression. This dynamic induced pulmonary artery smooth muscle cell proliferation and pulmonary vascular remodeling leading to pulmonary hypertension. A mutated motif in rats or a blocking peptide targeting this motif restrained HIMF binding with BMPR1A, rescued BMPR2 activity by ≈25% increase in Smad/1/5/9 phosphorylation and ≈39% elevation in Id-1 expression, and attenuated chronic hypoxia or sugen/hypoxia-induced pulmonary hypertension. CONCLUSIONS: HIMF induced pulmonary hypertension by direct binding to BMPR1A ectodomain, subsequently disrupting its binding to BMPR2 and BMPR2 activity. This HIMF signaling pathway represents a potential therapeutic target by selectively interfering with BMPR1A binding.
No takes yet. Share an insight, caveat, or question.
Zhang et al. (2025) studied Pulmonary hypertension. HIMF (hypoxia-induced mitogenic factor) and blocking peptide was evaluated on BMPR2 activity and pulmonary hypertension development. HIMF induces pulmonary hypertension by directly binding to the BMPR1A ectodomain and disrupting BMPR2 activity, a process that can be attenuated by a targeted blocking peptide.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: