CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension
Abstract Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis i...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-77388-5 |
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| author | Takahiro Hiraide Noboru Tsuda Mizuki Momoi Yoshiki Shinya Motoaki Sano Keiichi Fukuda Junji Shibahara Junko Kuramoto Yae Kanai Kenjiro Kosaki Yoji Hakamata Masaharu Kataoka |
| author_facet | Takahiro Hiraide Noboru Tsuda Mizuki Momoi Yoshiki Shinya Motoaki Sano Keiichi Fukuda Junji Shibahara Junko Kuramoto Yae Kanai Kenjiro Kosaki Yoji Hakamata Masaharu Kataoka |
| author_sort | Takahiro Hiraide |
| collection | DOAJ |
| description | Abstract Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis in patients with PAH. However, the molecular mechanisms of the RNF213 p.Arg4810Lys variant in development of PAH are unknown. We investigated the underlying molecular mechanisms of RNF213-associated vasculopathy using an in vivo mouse model. RNF213 +/p.Arg4828Lys mice, harboring the heterozygous RNF213 p.Arg4828Lys variant corresponding to the p.Arg4810Lys variant in humans, were created using the CRISPR-Cas9 system to recapitulate the genetic status of PAH patients. RNF213 +/p.Arg4828Lys mice had a significant elevation of the right ventricular systolic pressure, hypertrophy of the right ventricle, and increased thickness of the pulmonary arterial medial wall compared with wild-type mice after 3 months of exposure to a hypoxic environment. C-X-C motif chemokine ligand 12 (CXCL12), a C-X-C chemokine receptor type 4 (CXCR4) ligand, was significantly elevated in the lungs of RNF213 +/p.Arg4828Lys mice, and PAH was ameliorated by the administration of a CXCR4 antagonist. CXCL12-CXCR4 is an angiogenic chemokine axis, and immunohistochemistry demonstrated an increase in CXCR4 in vimentin-positive spindle-shaped cells in adventitia and interstitial lesions in RNF213 +/p.Arg4828Lys mice and lung specimens from severe PAH patients with the RNF213 p.Arg4810Lys variant. We confirmed a cause-and-effect relationship between the RNF213 p.Arg4810Lys variant and PAH via the CXCL12-CXCR4 pathway. The findings in this study suggest that targeting this pathway might be a novel therapeutic strategy for RNF213-associated vasculopathy. |
| format | Article |
| id | doaj-art-ad7f50c29ca34606974bcae82e0c24b5 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-ad7f50c29ca34606974bcae82e0c24b52024-11-10T12:16:20ZengNature PortfolioScientific Reports2045-23222024-11-0114111110.1038/s41598-024-77388-5CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertensionTakahiro Hiraide0Noboru Tsuda1Mizuki Momoi2Yoshiki Shinya3Motoaki Sano4Keiichi Fukuda5Junji Shibahara6Junko Kuramoto7Yae Kanai8Kenjiro Kosaki9Yoji Hakamata10Masaharu Kataoka11Department of Cardiology, Keio University School of MedicineDepartment of Pathology, Keio University School of MedicineDepartment of Cardiology, Keio University School of MedicineDepartment of Cardiology, Keio University School of Medicine Department of Medicine and Clinical Science, Yamaguchi University Graduate School of MedicineDepartment of Cardiology, Keio University School of MedicineDepartment of Pathology, School of Medicine, Kyorin UniversityDepartment of Pathology, Keio University School of MedicineDepartment of Pathology, Keio University School of MedicineCenter for Medical Genetics, Keio University School of MedicineDepartment of Basic Science, School of Veterinary Nursing and Technology, Faculty of Veterinary Science, Nippon Veterinary and Life Science UniversityDepartment of Cardiology, Keio University School of MedicineAbstract Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis in patients with PAH. However, the molecular mechanisms of the RNF213 p.Arg4810Lys variant in development of PAH are unknown. We investigated the underlying molecular mechanisms of RNF213-associated vasculopathy using an in vivo mouse model. RNF213 +/p.Arg4828Lys mice, harboring the heterozygous RNF213 p.Arg4828Lys variant corresponding to the p.Arg4810Lys variant in humans, were created using the CRISPR-Cas9 system to recapitulate the genetic status of PAH patients. RNF213 +/p.Arg4828Lys mice had a significant elevation of the right ventricular systolic pressure, hypertrophy of the right ventricle, and increased thickness of the pulmonary arterial medial wall compared with wild-type mice after 3 months of exposure to a hypoxic environment. C-X-C motif chemokine ligand 12 (CXCL12), a C-X-C chemokine receptor type 4 (CXCR4) ligand, was significantly elevated in the lungs of RNF213 +/p.Arg4828Lys mice, and PAH was ameliorated by the administration of a CXCR4 antagonist. CXCL12-CXCR4 is an angiogenic chemokine axis, and immunohistochemistry demonstrated an increase in CXCR4 in vimentin-positive spindle-shaped cells in adventitia and interstitial lesions in RNF213 +/p.Arg4828Lys mice and lung specimens from severe PAH patients with the RNF213 p.Arg4810Lys variant. We confirmed a cause-and-effect relationship between the RNF213 p.Arg4810Lys variant and PAH via the CXCL12-CXCR4 pathway. The findings in this study suggest that targeting this pathway might be a novel therapeutic strategy for RNF213-associated vasculopathy.https://doi.org/10.1038/s41598-024-77388-5 |
| spellingShingle | Takahiro Hiraide Noboru Tsuda Mizuki Momoi Yoshiki Shinya Motoaki Sano Keiichi Fukuda Junji Shibahara Junko Kuramoto Yae Kanai Kenjiro Kosaki Yoji Hakamata Masaharu Kataoka CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension Scientific Reports |
| title | CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension |
| title_full | CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension |
| title_fullStr | CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension |
| title_full_unstemmed | CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension |
| title_short | CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension |
| title_sort | cxcl12 cxcr4 pathway as a novel therapeutic target for rnf213 associated pulmonary arterial hypertension |
| url | https://doi.org/10.1038/s41598-024-77388-5 |
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