Viral vector-mediated overexpression of mitochondrial ATP-binding cassette subfamily B member7 does not protect against doxorubicin-induced cardiotoxicity

Autor: Imtiaz Masfique Dowllah, Branden Nguyen, Vivian Doerr, Cesar Jacintho Moritz, Ashley Smuder
Rok vydání: 2023
Předmět:
Zdroj: Physiology. 38
ISSN: 1548-9221
1548-9213
Popis: Doxorubicin (DOX)-induced cardiotoxicity results in an increased risk of mortality among chemotherapy recipients. Cardiomyocyte dysfunction is caused by the off-target accumulation of DOX in cardiac mitochondria, stimulating oxidative damage and impaired oxidative phosphorylation. Prior research showed that exercise preconditioning may prevent DOX-induced cardiotoxicity by enhancing the abundance of mitochondrial ATP-binding cassette (ABC) transporters, potentially accelerating the rate of DOX clearance from cardiomyocytes. Mitochondrial ABC subfamily B member7 (ABCB7) has been implicated in drug export and multidrug resistance. Therefore, to further understand whether, independent of exercise, overexpression of a mitochondria-localized ABC transporter can prevent acute cardiotoxic effects of DOX, we examined the effects of adeno-associated virus (AAV)-mediated overexpression of ABCB7 on cardiac function, exercise tolerance, and mitochondrial accumulation of DOX and its metabolites (doxorubicinol) in animals treated acutely with DOX (20 mg/kg IP). Female Sprague-Dawley rats were randomized into four experimental groups (n=10/ group): 1) Saline-treatment (CON), 2) DOX-treatment (DOX), 3) ABCB7 overexpression, saline-treatment (ABCB7), and 4) ABCB7 overexpression, DOX-treatment (ABCB7+DOX). Our findings show that DOX treatment results in detriments to left ventricular fractional shortening percentage 48 hours following administration, and overexpression of ABCB7 could partially protect from such DOX-induced dysfunction. However, the effect of ABCB7 overexpression on cardiac function was not related to a reduction in mitochondrial DOX and doxorubicinol concentration, nor does it improve exercise tolerance in acute DOX-treated animals. Further work is needed to elucidate the effects of ABCB7 on mitochondrial and cardiac function. Funding Source: R01 HL144858 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Databáze: OpenAIRE
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