Introduction: Cancer is independently associated with the alteration of cardiac function prior to cardiotoxic chemotherapy (CCT) exposure. Similar to cancer associated cachexia (CAC), the elevation and the deleterious role of IL-6 in plasma was associated with a reduced cardiac function in heart failure (HF) patients subpopulation. Cancer cells manipulate BCL-2-associated athanogene 3 (BAG3)-HSP70-regulated pathways in tumor cells, which is a key regulator of protein turnover and contractility in cardiomyocyte. Hypothesis: Here, we aimed to characterize the progression of cardiac dysfunction and the expression of BAG3 and HSP70 in tumor-bearing mice. Methods: Colon-26 adenocarcinoma cells (C26; n=22) with/without shIL-6 (C26 shIL-6; n=22) were injected subcutaneously adult male BALB/c mice. Control mice were injected with PBS (n=13). Echocardiographic examinations and invasive hemodynamic measurements ( in vivo and ex vivo using isolated working hearts system) were performed at 10 (early) and 20 (late) days post injection, respectively. The expression of BAG3 and Hsp70 were determined by Western blot. Results: The tumor size was comparable between the cancer groups. However, only C26 group showed a significant loss of subcutaneous fat and skeletal muscle (p<0.05, respectively), confirming cachectic condition. Echocardiography results show a tendency to decline of ejection fraction at the early phase (p~0.08 vs Control), and turned significance lower at late stage (p<0.05 vs Control) in tumor-bearing mice. In line with that, invasive hemodynamic and isolated working heart measurements confirmed LV systolic and diastolic dysfunction (late stage, p<0.05 vs Control, respectively). Interestingly, heart rate and aortic flow were predominantly declined in cachectic animals (p<0.05 vs Control). Importantly, cardiac dysfunction was associated with a significant reduction in both BAG3 and Hsp70 in the myocardium independently of cachexia. Conclusions: Cancer rather than CAC is a main driver for the development of cardiac contractile dysfunction prior to CCT exposure. In addition, our data suggest that targeting BAG3-Hsp70 complex in the cardiomyocytes may provide a novel strategy to improve the cancer associated cardiac dysfunction.
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Foundation The development of novel adjuvant angiogenic therapies to restore the low-perfused microvascular network upon myocardial infarction (MI) is crucial to avoid a possible end-stage heart failure. Of the current adult cell-based therapies, human adipose tissue-derived stromal vascular fraction cell (SVF) has vast reparative potential, principally due to: 1) its heterogeneous composition rich in mesenchymal stem cells (MSC), endothelial cells (EC), pericytes and hematopoietic cells, among others. In vitro engineering of SVF-based patches under unidirectional flow, applied by the help of a perfusion-based bioreactor, was found to increase certain cellular SVF subgroups such as pericytes, compared to static culture. In this study, we aimed at studying the potential of SVF-based engineered tissues in a model of chronic MI in nude rats. Human SVF cells were isolated upon liposuction and cultured on 3D collagen sponges (8 mm diameter, 3 mm thickness) either under constant unidirectional perfusion or in static condition for 5 days. Patches were characterized in terms of cellular composition prior to implantation. MI was induced by permanent ligation of the left anterior descending (LAD) coronary artery in male nude rats. Cardiac MRI was performed 4 weeks after MI; prior to the suture of patches and before sacrifice (4 weeks after implantation). Left ventricular ejection fraction (EF) was the surrogate marker and primary end point for cardiac pump function. Controls included untreated MI animals. Following perfusion culture, SVF cells were composed with a statistically superior percentage of pericytes, identified as CD45- CD34- CD146+ compared to static culture (28.06±10.03 and 3.37±2.50, respectively, p<0.0007). The presence of other cell subpopulations was similar in the patches generated in perfusion or static culture. While the percentage of EF at the time of sacrifice resulted to be not statistically different between static and perfusion-based patches, statically generated constructs showed a general trend of decrease in the % EF before and after treatment (rat 1: 61.96 vs 52.90; rat 2: 55.39 vs 53.00; rat 3: 52.34 vs 50.62, respectively). Perfusion-cultured patches, instead, rather improved the cardiac function, measured as % EF (rat 1: 51.82 vs 58.72; rat 2: 51.66 vs 60.45; rat 3: 53.50 vs 52. 36, respectively for 4 weeks following MI and 4 weeks following treatment). When comparing the ratio of the % EF 8 weeks and 4 weeks between static or perfusion-based patches and the untreated controls, rats treated with patches generated under perfusion resulted to show higher levels of % EF, with an almost statistically difference (p=0.0556), compared to the control group. The observed results showed the great potential of human SVF-based patches in the improvement of the heart pump function.
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