Resveratrol inhibits ferroptosis and decelerates heart failure progression via Sirt1/p53 pathway activation

Abstract

Resveratrol is an organic compound widely studied for its therapeutic uses. We investigated whether resveratrol exerts cardioprotective effects by inhibiting ferroptosis via the Sirt1/p53 pathway. A heart failure model was established by aortic coarctation in Sirt1 knockout mice. The superoxide dismutase (SOD), glutathione (GSH) levels and mitochondrial morphology in murine heart tissues were assessed at different time points to determine the role of ferroptosis in heart failure progression. The cardiac function of mice with heart failure was evaluated by determining the brain natriuretic peptide (BNP) and sST2 concentration and conducting echocardiography. Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) were transfected with the p53 K382R mutant and Sirt1 interference lentiviral vectors. Immunoprecipitation (IP) experiments were performed to investigate whether Sirt1 influences ferroptosis via p53 K382 acetylation and SLC7A11 expression modulation. Resveratrol improved cardiac function in mice and decelerated ferroptosis and fibrosis progression in heart failure. However, the ability of resveratrol to prevent ferroptosis and treat heart failure was lost after silencing Sirt1. Sirt1 reduced ferroptosis by diminishing the levels of p53 K382 acetylation, reducing the degradation of SLC7A11, and increasing the levels of GSH and glutathione peroxidase 4 (GPX4) in cells. In conclusion, by activating the Sirt1/p53 pathway in heart failure, resveratrol decreased the depletion of SLC7A11, inhibited ferroptosis, and improved cardiac function.

SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3

“…SIRT1-dependent p53 deacetylation is regarded as a crucial pathway to inhibit ferroptosis via regulation of SLC7A11 [ 43 ], but NAD + depletion caused by activated SIRT1 remains elusive in modulating ferroptosis. As an abundant metabolite, NAD+ is not only consumed by SIRT1 to deacetylate intracellular proteins, but also essential in maintenance of oxidative phosphorylation, fatty acid oxidation, and the TCA cycle [ 44 ].…”

SIRT1/P53 in retinal pigment epithelial cells in diabetic retinopathy: a gene co-expression analysis and He-Ying-Qing-Re formula treatment

“…SIRT1 can modulate cell senescence, cancer, and cellular reprogramming by deacetylating p53 ( Brockmueller et al, 2023 ; Lo Cigno et al, 2023 ). The joint effect of SIRT1/P53 could inhibit ferroptosis and apoptosis ( Zhang et al, 2023 ). In this study, we detected SIRT1 and P53 expression on immunofluorescence, Western blotting, and qRT-PCR aspects.…”

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines

“…[ 107 , 108 ] Additionally, the PI3K/Akt pathway also plays an important role in triggering cardiac fibrosis through activating ferroptosis in ischemic injury condition. [ 109 ] Recently, more and more ferroptosis signaling pathways have been found to participate in cardiac fibrosis, including TRIM44/TLR4/NOX4 signaling, [ 110 ] SIRT1/ P53 signaling, [ 111 ] SIRT3/P53 signaling, [ 112 ] NCOA4 mediated ferritinophagy, [ 113 ] et al . However, the above mainly focused on mechanisms affecting ferroptosis in fibrotic cardiac diseases, the mechanism by which ferroptosis leads to cardiac fibrosis remains largely unknown.…”