Abstract P1-08-05: Expression of the human APOE4 genotype modulates Doxorubicin cardiotoxicity in mice
| Autor: | Guannan Wang, G. William Rebeck, Olga Rodriguez, Marc E. Lippman, Nanette H. Bishopric |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Cancer Research. 82:P1-08 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.sabcs21-p1-08-05 |
| Popis: | Background: The human apolipoprotein E (APOE) gene has three major allelic variants: APOE2, -E3 and -E4. Carriers of the E4 allele are at increased risk for Alzheimer’s and other age-related neurodegenerative disorders. Recently, APOE4 has been associated with risk for cancer-related cognitive decline following chemotherapy with Doxorubicin (DOX), a frequent component of adjuvant therapy for breast cancer. To date, the mechanisms for APOE4 neurotoxicity are unknown, but may greater vulnerability to oxidative stress. DOX also causes dose-dependent cardiotoxicity, but a role for APOE4 in heart damage has not been previously demonstrated. Objective: To determine whether APOE4 predisposes to DOX-induced damage to the myocardium. Methods: C57Bl/6 mice (5-7 mo and 14-18 mo, male and female) with human APOE3 or APOE4 homozygous knock-in (=hAPOE3 and hAPOE4, respectively) were subjected to a single IP injection of saline (Control) or DOX (10 mg/kg, or 5 weekly injections of 5 mg/kg, =DOX), and monitored between 3-45 days afterward. Left ventricular systolic function was quantitated using echocardiography (Vevo 3100) at baseline, during and at the end of each study. TUNEL assay was used to identify apoptotic cells. Collagen was imaged using Masson’s Trichrome staining. Myocardial protein and RNA were extracted from the left ventricle and was analyzed by immunoblotting, realtime PCR and RNASeq on an Illumina NexGen platform.Results: Aged female APOE4 mice had more myocardial collagen at baseline (8.93±1.23 vs. 6.06±1.44%). Baseline cardiac function were similar at baseline in the 2 mouse strains. Three days after DOX, apoptotic myocytes were more abundant in hAPOE4 vs hAPOE3 hearts (1.2 vs. 4.6 TUNEL+ cells per section, n= 5, p Citation Format: Guannan Wang, G. William Rebeck, Olga Rodriguez, Marc E. Lippman, Nanette H. Bishopric. Expression of the human APOE4 genotype modulates Doxorubicin cardiotoxicity in mice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-05. |
| Databáze: | OpenAIRE |
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