Front Physiol. 2025 Jun 4;16:1628944. doi: 10.3389/fphys.2025.1628944. eCollection 2025.
ABSTRACT
[This retracts the article DOI: 10.3389/fphys.2019.01445.].
PMID:40534640 | PMC:PMC12175564 | DOI:10.3389/fphys.2025.1628944
Circ Heart Fail. 2025 Jun 19:e012479. doi: 10.1161/CIRCHEARTFAILURE.124.012479. Online ahead of print.
ABSTRACT
BACKGROUND: Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages.
METHODS: AAV-mediated cardiac gene transfer in pigs was performed by percutaneous catheter-based retrograde intravenous vector delivery, and vector genome and transgene expression levels determined by RT-PCR and immunoblotting. Postmyocardial infarction (MI) cardiac dysfunction porcine and murine models were generated by coronary catheter-based occlusion and ligation, respectively. The study end points left ventricular ejection fraction and left ventricular MI size, were measured by cardiac magnetic resonance imaging and echocardiography. Bulk myocardial RNA-sequencing and weighted gene correlation network analysis were used to link study end points to molecular pathway mechanisms. Safety was assessed by clinical chemistry, blood count and ECG.
RESULTS: In a first biodistribution study, AAV5 (1×1013 vector genomes; vgs) with the reporter gene luciferase (luc) achieved broad and homogenous transduction of healthy pig hearts 30 days after catheter-based retrograde intravenous vector delivery without toxicity. Both its myocardial and extra-cardiac distribution patterns were advantageous compared with AAV9-luc and AAV6-luc. Using AAV5 with the cardioprotective human gene S100A1 (hS100A1; 1×1013 vgcs) by catheter-based retrograde intravenous vector delivery in a subsequent therapy study in post-MI pigs prevented left ventricular MI extension and improved left ventricular ejection fraction after 3 months without clinical toxicity. Weighted gene correlation network analysis linked novel antiinflammatory actions and cardioprotective signaling mechanisms by S100A1 to study end point improvements, which was confirmed in a post-MI mouse model.
CONCLUSIONS: Providing the clinically relevant proof of oncept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility, and low preexisting immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease such as chronic heart failure, using therapeutic genetic effectors such as hS100A1 or others.
PMID:40534567 | DOI:10.1161/CIRCHEARTFAILURE.124.012479
Animal Model Exp Med. 2025 Jun 18. doi: 10.1002/ame2.70035. Online ahead of print.
ABSTRACT
BACKGROUND: There are many forms of anabolic steroids, including stanozolol (Winstrol), which are popular for their muscle-building effects but dangerous to the heart. This present work is aimed at evaluating the pharmacologica impact of allicin, a natural attribute obtained from garlic, on obstructing cardiac injury in rabbits that received stanozolol.
METHODS: Thirty rabbits were divided into three groups: control, stanozolol-treated, and stanozolol plus allicin. Cardiac function was assessed by measuring troponin, creatine kinase (CK), Galectin-3, and GDF-15. Oxidative stress and antioxidant markers, including malondialdehyde (MDA), glutathione, and catalase, were analyzed. Inflammatory mediators such as C-reactive protein (CRP), interleukin-6 (IL-6), NF-κB, iNOS, nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were evaluated. Lipid profile parameters, including total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), were measured. Histopathological examination assessed myocardial damage, fibrosis, and collagen deposition.
RESULTS: Stanozolol administration significantly increased cardiac damage markers, oxidative stress, and inflammatory mediators while causing dyslipidemia, characterized by elevated LDL and total cholesterol and reduced HDL. Allicin co-administration effectively countered these effects by reducing oxidative stress and inflammation, restoring antioxidant balance, and improving lipid profiles. Histopathological analysis revealed severe myocardial disorganization, necrosis, and fibrosis in the stanozolol group, whereas the allicin-treated group exhibited preserved myocardial structure with reduced collagen deposition.
CONCLUSION: Allicin significantly mitigates stanozolol-induced cardiotoxicity by reducing oxidative stress, inflammation, lipid dysregulation, and myocardial damage, as evidenced by biochemical and histopathological findings. These results suggest that allicin may serve as a potential therapeutic agent to counteract the cardiovascular risks associated with anabolic steroid use.
PMID:40534105 | DOI:10.1002/ame2.70035