Pharmacological SIRT1 Inhibition Exacerbates Angiotensin II-Induced Myocardial Injury and Is Associated with Dysregulation of the p53-FOXO3a Stress-Response Axis
| Author | Lijuan Song | en |
| Author | Umar Saeed | en |
| Author | Zahra Zahid Piracha | en |
| Author | Dilber Uzun Ozsahin | en |
| Author | İlker Özşahin | en |
| Author | Rizwan Uppal | en |
| Author | Muhammad Rehan Uppal | en |
| Author | Yunfan Gu | en |
| Issued Date | 2026-12-31 | en |
| Abstract | Background: Hypertensive myocardial injury is characterized by oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, largely driven by the central effector angiotensin II (Ang II). Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, coordinates stress-adaptive signaling; however, the effects of pharmacological SIRT1 inhibition on Ang II-induced stress are not fully defined. Objectives: To determine whether SIRT1 inhibition exacerbates Ang II–induced myocardial injury and to delineate the associated redox and mitochondrial changes and SIRT1-associated p53–Forkhead box O3a (FOXO3a) signaling alterations in cardiac cells. Methods: The primary outcome measures were cell viability, intracellular ROS accumulation, and mitochondrial membrane potential (ΔΨm), selected to characterize the core injury phenotype induced by Ang II and its modification by pharmacological SIRT1 inhibition. Secondary outcome measures included apoptotic injury markers, specifically the PARP cleavage index, BAX, Bcl-2, and cleaved caspase-3, along with inflammatory transcript responses assessed by quantitative polymerase chain reaction (qPCR) of TNF-α, IL-6, and NF-κB. Exploratory mechanistic outcomes included acetyl-p53 immunoblotting and analysis of FOXO3a nuclear–cytoplasmic localization to examine potential involvement of the SIRT1–p53–FOXO3a stress-response axis. Results: EX-527 significantly exacerbated the primary injury outcomes induced by Ang II, including reduced cell viability, increased ROS accumulation, and loss of mitochondrial membrane potential. Among the secondary outcomes, SIRT1 inhibition further increased the PARP cleavage index, enhanced BAX and cleaved caspase-3, suppressed Bcl-2, and augmented the Ang II–induced upregulation of inflammatory transcripts. Exploratory mechanistic analyses showed increased p53 acetylation and reduced nuclear enrichment of FOXO3a in the Ang II + EX-527 group, supporting involvement of the SIRT1–p53–FOXO3a axis in the aggravated injury phenotype. Conclusions: These pharmacological findings suggest that basal SIRT1 activity protects against Ang II–mediated myocardial injury by maintaining mitochondrial integrity and suppressing oxidative, apoptotic, and inflammatory cascades, with parallel changes in p53 acetylation and FOXO3a localization consistent with involvement of the p53–FOXO3a stress-response axis. However, causal validation of this pathway will require genetic and rescue-based studies. Pharmacological inhibition of SIRT1 aggravated Ang II–induced injury phenotypes in cardiac cell models, supporting SIRT1 activation as a potential therapeutic approach in hypertensive heart disease, although genetic validation remains required. | en |
| DOI | https://doi.org/10.5812/ijpr-170219 | en |
| URI | https://brieflands.com/journals/ijpr/articles/170219 | en |
| Keyword | Angiotensin II | en |
| Keyword | SIRT1 | en |
| Keyword | EX-527 | en |
| Keyword | Hypertension | en |
| Keyword | Oxidative Stress | en |
| Keyword | Mitochondrial Membrane Potential | en |
| Keyword | Apoptosis | en |
| Keyword | Inflammation | en |
| Keyword | P53 Acetylation | en |
| Keyword | FOXO3a | en |
| Publisher | Brieflands | en |
| Title | Pharmacological SIRT1 Inhibition Exacerbates Angiotensin II-Induced Myocardial Injury and Is Associated with Dysregulation of the p53-FOXO3a Stress-Response Axis | en |
| Type | Research Article | en |