Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/ijms23094675
Keywords
oxidative stress; rotenone; autophagy; autophagosome; Mn porphyrin
Funding
- Louisiana State University Health Sciences-Shreveport Intramural Grant [110101074A, HL141998, HL141998-01S1, AA025744, AA026708, AA025744-02S1, HL122354, HL145753, R25HL147665, P20GM12130]
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This study determined the role of a superoxide dismutase mimetic MnTnBuOE-2-PyP5+ (MnP) in the degradation of rotenone-induced 4-HNE aggresomes in HL-1 cardiomyocytes. The results showed that pre-treatment with MnP attenuated ROS formation, 4-HNE aggresome accumulation, and autophagosome formation induced by rotenone. Furthermore, MnP also reduced tubulin hyperacetylation and cell death caused by disruption of autophagy in HL-1 cells.
Reactive oxygen species (ROS) cause oxidative stress by generating reactive aldehydes known as 4-hydroxynonenal (4-HNE). 4-HNE modifies protein via covalent adduction; however, little is known about the degradation mechanism of 4-HNE-adducted proteins. Autophagy is a dynamic process that maintains cellular homeostasis by removing damaged organelles and proteins. In this study, we determined the role of a superoxide dismutase (SOD) mimetic MnTnBuOE-2-PyP5+ (MnP, BMX-001) on rotenone-induced 4-HNE aggresome degradation in HL-1 cardiomyocytes. A rotenone treatment (500 nM) given for 24 h demonstrated both increased ROS and 4-HNE aggresome accumulation in HL-1 cardiomyocytes. In addition, cardiomyocytes treated with rotenone displayed an increase in the autophagy marker LC3-II, as shown by immunoblotting and immunofluorescence. A pre-treatment with MnP (20 mu M) for 24 h attenuated rotenone-induced ROS formation. An MnP pre-treatment showed decreased 4-HNE aggresomes and LC3-II formation. A rotenone-induced increase in autophagosomes was attenuated by a pre-treatment with MnP, as shown by fluorescent-tagged LC3 (tfLC3). Rotenone increased tubulin hyperacetylation through the ROS-mediated pathway, which was attenuated by MnP. The disruption of autophagy caused HL-1 cell death because a 3-methyladenine inhibitor of autophagosomes caused reduced cell death. Yet, rapamycin, an inducer of autophagy, increased cell death. These results indicated that a pre-treatment with MnP decreased rotenone-induced 4-HNE aggresomes by enhancing the degradation process.
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