Dataset Information

Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection.

ABSTRACT:

Objectives

This study investigated how different concentrations of doxorubicin (DOX) can affect the function of cardiac cells. This study also examined whether activation of prokineticin receptor (PKR)-1 by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models.

Background

High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest.

Methods

This study used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EDPCs) for in vitro assays, tumor-bearing models, and acute and chronic toxicity mouse models for in vivo assays.

Results

Brief exposure to cardiomyocytes with high-dose DOX increased the accumulation of reactive oxygen species (ROS) by inhibiting a detoxification mechanism via stabilization of cytoplasmic nuclear factor, erythroid 2. Prolonged exposure to medium-dose DOX induced apoptosis in cardiomyocytes, ECs, and EDPCs. However, low-dose DOX promoted functional defects without inducing apoptosis in EDPCs and ECs. IS20 alleviated detrimental effects of DOX in cardiac cells by activating the serin threonin protein kinase B (Akt) or mitogen-activated protein kinase pathways. Genetic or pharmacological inactivation of PKR1 subdues these effects of IS20. In a chronic mouse model of DOX cardiotoxicity, IS20 normalized an elevated serum marker of cardiotoxicity and vascular and EDPC deficits, attenuated apoptosis and fibrosis, and improved the survival rate and cardiac function. IS20 did not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer, but it did attenuate the decreases in left ventricular diastolic volume induced by acute DOX treatment.

Conclusions

This study identified the molecular and cellular signature of dose-dependent, DOX-mediated cardiotoxicity and provided evidence that PKR-1 is a promising target to combat cardiotoxicity of cancer treatments.

SUBMITTER: Gasser A

PROVIDER: S-EPMC8352030 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection.

Gasser Adeline A Chen Yu-Wen YW Audebrand Anais A Daglayan Ayhan A Charavin Marine M Escoubet Brigitte B Karpov Pavel P Tetko Igor I Chan Michael W Y MWY Chan Michael W Y MWY Cardinale Daniela D Désaubry Laurent L Nebigil Canan G CG

JACC. CardioOncology 20190710 1

<h4>Objectives</h4>This study investigated how different concentrations of doxorubicin (DOX) can affect the function of cardiac cells. This study also examined whether activation of prokineticin receptor (PKR)-1 by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models.<h4>Background</h4>High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest.<h4>Methods</h4>This study used cultured c ...[more]

PMID: 34396166

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Project description:BackgroundThe release of proinflammatory cytokines is inhibited by propofol, which could reduce oxidative stress and suggests that propofol could ameliorate the adverse effects of anthracyclines in myocardial cells as a promising cardioprotective agent. The aim of the study was to evaluate the protective effects of propofol on phosphatidylinositol 3 kinase/protein kinase B/B cell lymphoma 2 (PI3K/AKT/Bcl-2) pathway in cardiomyocyte apoptosis induced by doxorubicin [adriamycin (ADM)] of rat cardiomyocytes in vivo.MethodsThe 40 F344 female rats were randomly divided into 4 groups (n=10): treatment control, ADM, Propofol (Prop) and ADM + Prop group. Blood samples were taken as baseline, before the 4th administration of the agents and before humane death. The serum levels of malondialdehyde (MDA), an oxidant factor, were detected by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were analyzed by xanthine oxidase, and those of cardiac troponin I (cTnI), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) were analyzed by enzyme linked immunosorbent assay (ELISA). Apoptosis of cardiac myocytes was measured by flow cytometry. The expression levels of PI3K-110α and pAKT-Ser473 and Bcl-2 proteins in rat heart tissue were detected by western blot.ResultsApoptosis induced by ADM was significantly reduced by propofol. Compared with the ADM group, the serum levels of MDA, cTnI and BNP in the ADM + Prop group were significantly downregulated. In addition, the PI3K-110α and pAKT-Ser473 expressions in the ADM group were significantly higher than those in the ADM + Prop group, and the increases in Bcl-2 expression in the ADM + Prop group was statistically significant compared with the ADM group.ConclusionsWe identified that the PI3K/AKT/Bcl-2 axis is involved in the regulation of cardiomyocyte apoptosis induced by ADM in vivo. In addition, our results elucidated that propofol had a protective role in cardiomyocyte apoptosis induced by ADM by suppressing the PI3K/AKT/Bcl-2 pathway.

Dataset Information

Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection.

Objectives

Background

Methods

Results

Conclusions

Publications

Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection.

Similar Datasets

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