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circMFN2 Regulates the IGF2BP3-PDK4 to Ameliorate Pulmonary Hypertension
Shan-Shan Li1, Miao Guo1, Ying Zhao1
1School of Medicine, Nankai University, Tianjin, China (S.-S.L., M.G., Y.Z., S.H., Y.Y., Y.C., X.J.).
Background:
Circular RNAs have emerged as key regulators of vascular remodeling and promising therapeutic targets, yet their specific contributions to pulmonary hypertension (PH) remain largely unknown.
Methods:
We identified a PH-related circular RNA, circMFN2, generated from the MFN2 (mitofusin-2) locus, which was significantly downregulated in the peripheral blood of patients with PH and in pulmonary arteries of Sugen/hypoxia-induced PH mice. Functional studies were performed in human pulmonary artery smooth muscle cells under hypoxic conditions and in Sugen/hypoxia mice treated intranasally with R8-circMFN2 (R8-peptide-modified liposomal circMFN2). Transcriptomic profiling, RNA-protein interaction assays, and mitochondrial function analyses were used to define the downstream mechanisms.
Results:
circMFN2 overexpression significantly attenuated hypoxia-induced human pulmonary artery smooth muscle cell proliferation, migration, and mitochondrial dysfunction. RNA sequencing after circMFN2 knockdown revealed activation of gene networks associated with respiratory system diseases. Mechanistically, circMFN2 directly bound the RNA-binding protein IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3), thereby blocking its stabilization of PDK4 (pyruvate dehydrogenase kinase 4) mRNA. This circMFN2-IGF2BP3-PDK4 regulatory axis limited PDK4-mediated metabolic reprogramming, restored mitochondrial fusion, reduced reactive oxygen species, and normalized oxidative phosphorylation. In Sugen/hypoxia mice, therapeutic intranasal delivery of R8-circMFN2 significantly improved pulmonary hemodynamics, reduced vascular remodeling, and downregulated PDK4 expression.
Conclusions:
circMFN2 functions as a hypoxia-responsive regulator that preserves mitochondrial homeostasis by restraining the IGF2BP3-PDK4 axis. Intranasal delivery of R8-circMFN2 establishes a translational potential for noninvasive circular RNA-based therapy to reverse pulmonary vascular remodeling and hemodynamic impairment in PH.
Insights
Circular RNA circMFN2 is downregulated in pulmonary hypertension (PH). Restoring circMFN2 in mice reversed PH-related vascular remodeling and improved hemodynamics, showing therapeutic potential.
Area of Science:
- Vascular Biology
- Mitochondrial Biology
- RNA Biology
Background:
- Circular RNAs (circRNAs) are emerging regulators of vascular remodeling with unknown roles in pulmonary hypertension (PH).
- This study investigates the role of circMFN2 in PH pathogenesis.
Purpose of the Study:
- To identify and characterize circRNAs involved in PH.
- To elucidate the molecular mechanisms of circMFN2 in PH.
- To evaluate the therapeutic potential of circMFN2 in PH.
Main Methods:
- Identified circMFN2, downregulated in PH patients and mouse models.
- Utilized human pulmonary artery smooth muscle cells and a mouse model of PH.
- Employed transcriptomic profiling, RNA-protein interaction assays, and mitochondrial function analyses.
- Investigated the circMFN2-IGF2BP3-PDK4 regulatory axis.
Main Results:
- circMFN2 overexpression attenuated hypoxia-induced smooth muscle cell proliferation, migration, and mitochondrial dysfunction.
- circMFN2 directly bound IGF2BP3, inhibiting PDK4 mRNA stabilization.
- This axis restored mitochondrial homeostasis and reduced PH hallmarks in mice.
- Therapeutic intranasal delivery of R8-circMFN2 improved pulmonary hemodynamics and vascular remodeling.
Conclusions:
- circMFN2 acts as a hypoxia-responsive regulator preserving mitochondrial homeostasis via the IGF2BP3-PDK4 axis.
- Noninvasive intranasal delivery of R8-circMFN2 shows translational potential for PH therapy.
- circMFN2-based therapy can reverse pulmonary vascular remodeling and hemodynamic impairment in PH.
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