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Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis.
- Source :
-
Molecular medicine (Cambridge, Mass.) [Mol Med] 2023 Jul 06; Vol. 29 (1), pp. 91. Date of Electronic Publication: 2023 Jul 06. - Publication Year :
- 2023
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Abstract
- Background: E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape of genes involved in multiple cardiovascular diseases. Ferroptosis of vascular smooth muscle cells (VSMCs) is a novel pathological mechanism of aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown.<br />Methods: Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used to induce VSMC ferroptosis. Two different knockdown plasmids targeting P300 and A-485 (a specific inhibitor of P300) were used to investigate the function of P300 in the ferroptosis of human aortic smooth muscle cells (HASMCs). Cell counting kit-8, lactate dehydrogenase and flow cytometry with propidium iodide staining were performed to assess the cell viability and death under the treatment of CD and IKE. BODIPY-C11 assay, immunofluorescence staining of 4-hydroxynonenal and malondialdehyde assay were conducted to detect the level of lipid peroxidation. Furthermore, co-immunoprecipitation was utilized to explore the interaction between P300 and HIF-1α, HIF-1α and P53.<br />Results: Compared with normal control, the protein level of P300 was significantly decreased in HASMCs treated with CD and IKE, which was largely nullified by the ferroptosis inhibitor ferrostatin-1 but not by the autophagy inhibitor or apoptosis inhibitor. Knockdown of P300 by short-hairpin RNA or inhibition of P300 activity by A-485 promoted CD- and IKE-induced HASMC ferroptosis, as evidenced by a reduction in cell viability and aggravation of lipid peroxidation of HASMCs. Furthermore, we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway was responsible for the impacts of P300 on ferroptosis of HASMCs. The results of co-immunoprecipitation demonstrated that P300 and P53 competitively bound HIF-1α to regulate the expression of HMOX1. Under normal conditions, P300 interacted with HIF-1α to inhibit HMOX1 expression, while reduced expression of P300 induced by ferroptosis inducers would favor HIF-1α binding to P53 to trigger HMOX1 overexpression. Furthermore, the aggravated effects of P300 knockdown on HASMC ferroptosis were largely nullified by HIF-1α knockdown or the HIF-1α inhibitor BAY87-2243.<br />Conclusion: Thus, our results revealed that P300 deficiency or inactivation facilitated CD- and IKE-induced VSMC ferroptosis by activating the HIF-1α/HMOX1 axis, which may contribute to the development of diseases related to VSMC ferroptosis.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Heme Oxygenase-1 genetics
Heme Oxygenase-1 metabolism
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Myocytes, Smooth Muscle metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Ferroptosis
Muscle, Smooth, Vascular metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-3658
- Volume :
- 29
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular medicine (Cambridge, Mass.)
- Publication Type :
- Academic Journal
- Accession number :
- 37415103
- Full Text :
- https://doi.org/10.1186/s10020-023-00694-7