Abstract
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. 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. 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.
Highlights
Understanding the mechanisms underlying cardiac failure in the context of cancer has the potential to reduce morbidity and chemotherapy-associated cardiac toxicity
Cramer et al showed that patients with colorectal cancer had reduced left ventricular (LV) ejection fraction, peak oxygen consumption, and higher levels of the endothelium-derived Cterminal-pro-endothelin-1, independent of chemotherapy[2]
Echocardiography reveals impaired heart function in male but not female LLC1 tumor-bearing mice 14 days post LLC1 tumor cell or PBS vehicle injection, heart echocardiography showed that tumor-bearing male mice had significantly thinner LV posterior walls (LVPW, 0.628 ± 0.04 mm systole and 0.482 ± 0.03 mm diastole) compared to vehicle-injected mice (1.122 ± 0.04 mm systole and 0.698 ± 0.01 mm diastole; both p < 0.0001, Fig 1A and 1B)
Summary
Understanding the mechanisms underlying cardiac failure in the context of cancer has the potential to reduce morbidity and chemotherapy-associated cardiac toxicity. There is a need to understand the mechanisms of cardiac dysfunction in the context of chemotherapynaive cancer patients in order to develop therapies that can mitigate cancer associated heart failure and identify those at increased risk of chemotherapy-induced heart failure. 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. 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). 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.
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