Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function
Background The complex interplay between vascular contractility and mitochondrial function is central to cardiovascular disease. The progranulin gene (GRN) encodes glycoprotein PGRN (progranulin), a ubiquitous molecule with known anti‐inflammatory property. However, the role of PGRN in cardiovascula...
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| Language: | English |
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Wiley
2025-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.037640 |
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| author | Shubhnita Singh Ariane Bruder Rafael M. Costa Juliano V. Alves Sivakama Bharathi Eric S. Goetzman Thiago Bruder‐Nascimento |
| author_facet | Shubhnita Singh Ariane Bruder Rafael M. Costa Juliano V. Alves Sivakama Bharathi Eric S. Goetzman Thiago Bruder‐Nascimento |
| author_sort | Shubhnita Singh |
| collection | DOAJ |
| description | Background The complex interplay between vascular contractility and mitochondrial function is central to cardiovascular disease. The progranulin gene (GRN) encodes glycoprotein PGRN (progranulin), a ubiquitous molecule with known anti‐inflammatory property. However, the role of PGRN in cardiovascular disease remains undefined. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality. Methods and Results We used aortae from male and female C57BL6/J wild‐type (PGRN+/+) and B6(Cg)‐Grntm1.1Aidi/J (PGRN−/−) mice. Our results showed suppression of contractile activity in PGRN−/−, followed by reduced α‐smooth muscle actin expression. Mechanistically, PGRN deficiency suppressed mitochondrial respiration, induced mitochondrial fission, and disturbed autophagy process and redox signaling, while restoration of PGRN levels in aortae from PGRN−/− mice via lentivirus delivery ameliorated contractility and boosted mitochondria activity. In addition, in vivo treatment with mitochondrial fission inhibitor restored mitochondrial quality and vascular contractility, while vascular smooth muscle cells overexpressing PGRN displayed higher lysosome biogenesis, accelerated mitophagy flux, and mitochondrial respiration accompanied by vascular hypercontractility. Finally, angiotensin II failed to induce vascular contractility in PGRN−/−, suggesting a key role of PGRN to maintain the vascular tone. Conclusions Our findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial activity and dynamics, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in cardiovascular disease. |
| format | Article |
| id | doaj-art-0b816b1c031548d5b99f785f1f576d2f |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-0b816b1c031548d5b99f785f1f576d2f2025-02-04T11:00:01ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-02-0114310.1161/JAHA.124.037640Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial FunctionShubhnita Singh0Ariane Bruder1Rafael M. Costa2Juliano V. Alves3Sivakama Bharathi4Eric S. Goetzman5Thiago Bruder‐Nascimento6Department of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PADepartment of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PADepartment of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PADepartment of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PADepartment of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PADepartment of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PADepartment of Pediatrics at UPMC Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh PABackground The complex interplay between vascular contractility and mitochondrial function is central to cardiovascular disease. The progranulin gene (GRN) encodes glycoprotein PGRN (progranulin), a ubiquitous molecule with known anti‐inflammatory property. However, the role of PGRN in cardiovascular disease remains undefined. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality. Methods and Results We used aortae from male and female C57BL6/J wild‐type (PGRN+/+) and B6(Cg)‐Grntm1.1Aidi/J (PGRN−/−) mice. Our results showed suppression of contractile activity in PGRN−/−, followed by reduced α‐smooth muscle actin expression. Mechanistically, PGRN deficiency suppressed mitochondrial respiration, induced mitochondrial fission, and disturbed autophagy process and redox signaling, while restoration of PGRN levels in aortae from PGRN−/− mice via lentivirus delivery ameliorated contractility and boosted mitochondria activity. In addition, in vivo treatment with mitochondrial fission inhibitor restored mitochondrial quality and vascular contractility, while vascular smooth muscle cells overexpressing PGRN displayed higher lysosome biogenesis, accelerated mitophagy flux, and mitochondrial respiration accompanied by vascular hypercontractility. Finally, angiotensin II failed to induce vascular contractility in PGRN−/−, suggesting a key role of PGRN to maintain the vascular tone. Conclusions Our findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial activity and dynamics, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in cardiovascular disease.https://www.ahajournals.org/doi/10.1161/JAHA.124.037640progranulinvascular contractilityvasculature |
| spellingShingle | Shubhnita Singh Ariane Bruder Rafael M. Costa Juliano V. Alves Sivakama Bharathi Eric S. Goetzman Thiago Bruder‐Nascimento Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease progranulin vascular contractility vasculature |
| title | Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function |
| title_full | Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function |
| title_fullStr | Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function |
| title_full_unstemmed | Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function |
| title_short | Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function |
| title_sort | vascular contractility relies on integrity of progranulin pathway insights into mitochondrial function |
| topic | progranulin vascular contractility vasculature |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.037640 |
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