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A Mechanistic Omics‐based Evaluation of Mitochondria‐targeting‐H2S‐donor (AP39) Against Doxorubicin Cardiotoxicity
Author(s) -
Veeranki Sudhakar,
Scott David A.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01977
Subject(s) - cardiotoxicity , doxorubicin , mitochondrion , pharmacology , cardioprotection , medicine , cancer research , chemistry , biochemistry , biology , bioinformatics , toxicity , chemotherapy , myocardial infarction
Use of the highly effective broad‐spectrum anti‐cancer chemotherapeutic agent, doxorubicin (Dox), induces Dox‐induced cardiotoxicity (DIC) which leads to mortality and morbidity in pediatric cancer survivors. Dox treatment alters cardiac metabolism and mitochondrial function, however, underlying mechanisms and prevention strategies have not yet been discovered, which limits Dox’s broad clinical utilization. Our data demonstrated that Dox, along with mitochondrial toxicity, depleted both mitochondrial hydrogen sulfide (H 2 S) and mitochondrial localized H 2 S producing enzyme, 3‐mercaptopyruvate sulfurtransferase (MPST). As H 2 S is a cardioprotective signaling molecule, we tested the ability of mitochondria‐targeting‐H 2 S‐donor, AP39, to protect from the DIC. AP39 treatment was highly effective in mitigating the DIC in mouse models. Further, the combined use of RNAseq, targeted metabolomics and 13C‐labeled‐glucose‐isotope tracing approaches in a cardiomyoblast cell line revealed that AP39 conferred protection against dox‐toxicity by reversing key transcriptional and metabolic features. Moreover, there were improvements in mitochondrial antioxidant status, H 2 S presence, and quality control. Thus, AP39 is instrumental in protecting mitochondria and promoting stress‐resistant metabolism against DIC. In summary, the integrated omics‐based approach revealed that AP39 confers potent cardioprotection against DIC. Support or Funding Information The study was supported by the funds from the American heart association award# 17SDG33670578 to Dr. Veeranki. Dr. Veeranki is also supported by NIH grant HL131782 to Douglas Andres (D.A.) and Jonathan Satin (J.S.) (University of Kentucky). We thank Bryana Levitan (University of Kentucky) for the help with Echocardiography. We thank D.A. and J.S. for sharing some reagents. We thank Markey cancer center RM SRF (supported by NCI Cancer Center Support Grant (P30 CA177558)) for the help with OCR assays. The Vevo 3100 was supported by the Saha Cardiovascular Research Center.