Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice
Autoři:
Taylor E. Berent aff001; Jessica M. Dorschner aff001; Thomas Meyer aff001; Theodore A. Craig aff001; Xuewei Wang aff002; Hawley Kunz aff003; Aminah Jatoi aff004; Ian R. Lanza aff003; Horng Chen aff005; Rajiv Kumar aff001
Působiště autorů:
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United states of America
aff001; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America
aff002; Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
aff003; Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, United States of America
aff004; Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, United States of America
aff005; Department of Biochemistry and Molecular Biology; Mayo Clinic, Rochester, Minnesota, United States of America
aff006
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0226440
Souhrn
Background
To understand the underlying mechanisms of cardiac dysfunction in cancer, we examined cardiac function, protein synthesis, mitochondrial function and gene expression in a model of heart failure in mice injected with Lewis lung carcinoma (LLC1) cells.
Experimental design
Seven week-old C57BL/J6 male and female mice were injected with LLC1 cells or vehicle. Cardiac ejection fraction, ventricular wall and septal thickness were reduced in male, but not female, tumor-bearing mice compared to vehicle-injected control mice. Cardiac protein synthesis was reduced in tumor-bearing male mice compared to control mice (p = 0.025). Aspect ratio and form factor of cardiac mitochondria from the tumor-bearing mice were increased compared control mice (p = 0.042 and p = 0.0032, respectively) indicating a more fused mitochondrial network in the hearts of tumor-bearing mice. In cultured cardiomyocytes maximal oxygen consumption and mitochondrial reserve capacity were reduced in cells exposed to tumor cell-conditioned medium compared to non-conditioned medium (p = 0.0059, p = 0.0010). Whole transcriptome sequencing of cardiac ventricular muscle from tumor-bearing vs. control mice showed altered expression of 1648 RNA transcripts with a false discovery rate of less than 0.05. Of these, 54 RNA transcripts were reduced ≤ 0.5 fold, and 3 RNA transcripts were increased by ≥1.5-fold in tumor-bearing mouse heart compared to control. Notably, the expression of mRNAs for apelin (Apln), the apelin receptor (Aplnr), the N-myc proto-oncogene, early growth protein (Egr1), and the transcription factor Sox9 were reduced by >50%, whereas the mRNA for growth arrest and DNA-damage-inducible, beta (Gadd45b) is increased >2-fold, in ventricular tissue from tumor-bearing mice compared to control mice.
Conclusions
Lung tumor cells induce heart failure in male mice in association with reduced protein synthesis, mitochondrial function, and the expression of the mRNAs for inotropic and growth factors. These data provide new mechanistic insights into cancer-associated heart failure that may help unlock treatment options for this condition.
Klíčová slova:
Cardiovascular physiology – Messenger RNA – Mitochondria – Mouse models – Oxygen consumption – Protein synthesis
Zdroje
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