Academic Journal
Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function.
| Τίτλος: | Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function. |
|---|---|
| Συγγραφείς: | Singh S; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA.; Children's Hospital of Philadelphia (CHOP) Department of Genetics at the University of Pennsylvania School of Medicine Philadelphia PA.; Department of Human Genetics, School of Public Health University of Pittsburgh PA., Bruder A; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA.; Department of Physiology & Cell Biology, School of Medicine University of South Alabama Mobile AL., Costa RM; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA.; Department of Physiology & Cell Biology, School of Medicine University of South Alabama Mobile AL., Alves JV; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA., Bharathi S; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA., Goetzman ES; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA.; Department of Human Genetics, School of Public Health University of Pittsburgh PA.; Genetic and Genomic Medicine Division at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA., Bruder-Nascimento T; Department of Pediatrics at UPMC Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh PA.; Department of Physiology & Cell Biology, School of Medicine University of South Alabama Mobile AL. |
| Πηγή: | Journal of the American Heart Association [J Am Heart Assoc] 2025 Feb 04; Vol. 14 (3), pp. e037640. Date of Electronic Publication: 2025 Feb 03. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101580524 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2047-9980 (Electronic) Linking ISSN: 20479980 NLM ISO Abbreviation: J Am Heart Assoc Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Oxford : Wiley-Blackwell |
| Ιατρικοί όροι (MeSH): | Progranulins*/genetics , Progranulins*/metabolism , Progranulins*/deficiency , Muscle, Smooth, Vascular*/metabolism , Muscle, Smooth, Vascular*/physiopathology , Vasoconstriction*/physiology , Aorta*/metabolism , Aorta*/physiopathology , Myocytes, Smooth Muscle*/metabolism , Mitochondria, Muscle*/metabolism , Mitochondria*/metabolism, Animals ; Male ; Mice, Inbred C57BL ; Female ; Signal Transduction ; Mice, Knockout ; Mice ; Mitochondrial Dynamics ; Mitophagy ; Autophagy |
| Περίληψη: | 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. |
| Σχόλια: | Update of: bioRxiv. 2023 Nov 01:2023.10.27.564485. doi: 10.1101/2023.10.27.564485.. (PMID: 37961631) |
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| Grant Information: | R00 HL140139 United States HL NHLBI NIH HHS; R01 HL169202 United States HL NHLBI NIH HHS |
| Contributed Indexing: | Keywords: progranulin; vascular contractility; vasculature |
| Substance Nomenclature: | 0 (Progranulins) 0 (Grn protein, mouse) |
| Entry Date(s): | Date Created: 20250203 Date Completed: 20250505 Latest Revision: 20260723 |
| Update Code: | 20260723 |
| PubMed Central ID: | PMC12074767 |
| DOI: | 10.1161/JAHA.124.037640 |
| PMID: | 39895524 |
| Βάση Δεδομένων: | MEDLINE |
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