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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Mrp1 localization and function in cardiac mitochondria after doxorubicin
Paiboon Jungsuwadee1, Ramaneeya Nithipongvanitch, Yumin Chen
1Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA.
Molecular Pharmacology
|February 24, 2009
Summary
Multidrug resistance-associated protein 1 (Mrp1) moves to mitochondria after doxorubicin treatment, likely protecting heart cells from oxidative stress. However, oxidative damage impairs Mrp1 function.
Area of Science:
- Biochemistry
- Cardiology
- Molecular Biology
Background:
- Multidrug resistance-associated protein 1 (Mrp1; Abcc1) is found in cardiac sarcolemma, potentially protecting cardiomyocytes from toxins.
- Doxorubicin (DOX) induces cardiotoxicity via oxidative stress, making it a relevant model for studying cardiac protection mechanisms.
Purpose of the Study:
- To investigate the localization and function of Mrp1 in the heart following doxorubicin-induced cardiotoxicity.
- To determine if Mrp1 plays a role in mitigating DOX-induced oxidative stress in cardiac mitochondria.
Main Methods:
- Confocal immunofluorescence and immunogold electron microscopy to localize Mrp1.
- Subcellular fractionation, immunoblot analysis, and transport assays to assess Mrp1 expression and activity.
- Detection of protein adduction with 4-hydroxy-2-nonenal (HNE) to evaluate oxidative damage.
Main Results:
- Doxorubicin treatment increased Mrp1 expression in heart homogenate, sarcolemma, and submitochondrial particles (SMP).
- Functional Mrp1 was localized to mitochondria after DOX exposure, with peak transport activity in SMP at 24 hours.
- Mrp1-HNE adduction was observed in SMP, correlating with increased oxidative stress, and HNE inhibited Mrp1 activity in vitro.
Conclusions:
- Doxorubicin induces a shift in functional Mrp1 localization to cardiac mitochondria, suggesting a protective role against oxidative stress.
- Oxidative stress, indicated by HNE adduction, impairs mitochondrial Mrp1 activity, potentially contributing to cardiotoxicity.
- Mrp1 may protect cardiomyocytes by exporting toxic products of oxidative stress from mitochondria.
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