Mandatory role of endoplasmic reticulum and its pentose phosphate shunt in the myocardial defense mechanisms against the redox stress induced by anthracyclines.

Autor: Sambuceti G; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., Cossu V; Department of Experimental Medicine, Human Anatomy Section, University of Genoa, 16132, Genoa, Italy. vanessa.cossu@edu.unige.it., Vitale F; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Bianconi E; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Carta S; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Venturi C; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Chiesa S; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Lanfranchi F; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., Emionite L; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Carlone S; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Sofia L; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., D'Amico F; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., Di Raimondo T; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., Chiola S; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Orengo AM; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy., Morbelli S; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., Ameri P; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.; Department of Internal Medicine, University of Genoa, 16132, Genoa, Italy., Bauckneht M; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.; Department of Health Sciences, University of Genoa, 16132, Genoa, Italy., Marini C; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.; Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), 20054, Milan, Italy.
Jazyk: angličtina
Zdroj: Molecular and cellular biochemistry [Mol Cell Biochem] 2024 Nov; Vol. 479 (11), pp. 2973-2987. Date of Electronic Publication: 2023 Dec 12.
DOI: 10.1007/s11010-023-04903-z
Abstrakt: Anthracyclines' cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD -/- ). Twenty-eight wildtype (WT) and 32 H6PD -/- mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18 F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca 2+ -ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD -/- died. At microPET, DXR-H6PD -/- survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD -/- condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca 2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca 2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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