| Title: |
PERM1 Gene Delivery via AAV Prevents Heart Failure in a Mouse Model of Pressure Overload |
| Authors: |
Sreedevi, Karthi; Montalvo, Ryan; Doku, Abbigail; Korte, Audrey; Thomas, Rebekah; Salama, Sarah; Burrows, Steven; Yan, Zhen; Zaitsev, Alexey V.; Warren, Junco S. |
| Publication Year: |
2025 |
| Collection: |
VTechWorks (VirginiaTech) |
| Subject Terms: |
AAV; Cardiac contractility; Creatine kinase; Gene therapy; HFrEF; Heart failure; Mitochondrial bioenergetics; O-GlcNAcylation; PERM1 |
| Description: |
Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of mortality worldwide. A hallmark of HFrEF is impaired cardiomyocyte contractility accompanied by disrupted mitochondrial bioenergetics; however, no current therapy targets both pathologies simultaneously. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is downregulated in HFrEF patients. We recently demonstrated that overexpression of PERM1 via adeno-associated virus 9 (AAV9-PERM1) enhances both cardiac contractility and mitochondrial biogenesis in C57BL/6 mice. In this study, we evaluated the therapeutic potential of AAV9-PERM1 in a pressure overload-induced mouse model of HFrEF. C57BL/6 mice were treated with either AAV9-PERM1 or control AAV9-GFP (1×1012 GC/mouse), followed by transverse aortic constriction (TAC) surgery. At 4 weeks post-TAC, control mice receiving AAV-GFP exhibited reduced left ventricular ejection fraction (LVEF), whereas AAV-PERM1 preserved LVEF at baseline levels. This cardioprotective effect was sustained through 8 weeks. Notably, AAV9-PERM1 completely abrogated TAC-induced cardiac hypertrophy and fibrosis. Mitochondrial analysis revealed that AAV9-PERM1 preserved mitochondrial DNA copy number and TFAM protein levels, both of which were reduced by TAC in control hearts. AAV9-PERM1 also improved mitochondrial respiration using pyruvate and octanoylcarnitine as substrates and prevented TAC-induced impairments in oxidative capacity. While PGC-1 expression remained unchanged in control TAC hearts, it was modestly yet significantly upregulated by AAV9-PERM1 in both sham and TAC groups. In addition, AAV9-PERM1 suppressed TACinduced increases in O-GlcNAcylation, a stress-related posttranslational modification of proteins. Coimmunoprecipitation further revealed interactions of PERM1 with creatine kinase and troponin C, key proteins in ATP transduction and contractility, suggesting a functional coupling between mitochondrial energetics and contractility. In conclusion, AAV-PERM1 gene therapy ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.ncbi.nlm.nih.gov/pubmed/41256646; https://hdl.handle.net/10919/140743; https://doi.org/10.1101/2025.09.29.679055 |
| DOI: |
10.1101/2025.09.29.679055 |
| Availability: |
https://hdl.handle.net/10919/140743; https://doi.org/10.1101/2025.09.29.679055 |
| Rights: |
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International ; http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.65D41FA3 |
| Database: |
BASE |