PO.PR02.03 · 预防研究
高蔗糖摄入放大并独立促进幼龄小鼠模型中蒽环类药物诱导的心脏功能障碍和衰老
High sucrose intake amplifies and independently promotes anthracycline-induced cardiac dysfunction and senescence in juvenile mouse models
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
蒽环类药物如多柔比星（dox）是一类有效的化疗药物，常用于青少年和青年（AYA）癌症患者，但与心脏毒性相关。通过可改变的行为来减轻心脏晚期效应具有全球性和成本效益的益处，但影响潜在获益的参数仍不明确。在此，我们研究了蔗糖摄入对dox诱导的心脏毒性和衰老在体内的影响。给雄性和雌性p16/3MR转基因小鼠提供正常（NSW，0%）或高（HSW，45%）蔗糖水，并使用dox（2.5 mg/kg，尾静脉注射×4剂）处理。通过超声心动图评估心脏功能，以测量射血分数（EF）和缩短分数（FS）。采用qRT-PCR定量心脏miR-1a和miR-499的表达，并通过红色荧光蛋白（RFP）信号在心脏组织中可视化衰老细胞的积累。高蔗糖摄入加重了dox相关的射血分数降低，其中HSW+dox组表现出最大的功能下降，这一模式在治疗后4周（p = 0.0187）和6周（p = 0.0353）具有统计学意义。值得注意的是，单独高蔗糖相对于NSW对照也降低了EF，表明饮食诱导的心脏功能损害。dox处理升高了心脏组织中心肌应激的生物标志物（miR-1a和miR-499），而单独高蔗糖产生了相当的上调。以RFP荧光测量的衰老在dox暴露和蔗糖暴露的心脏中均增加。有趣的是，与dox对照和饮食对照相比，HSW+dox组表现出最高的RFP信号，表明衰老的协同增强，提示分子衰老标志物可能捕捉到功能下降之前的早期损伤。高膳食蔗糖既放大又独立地损害心脏功能并增加衰老，蔗糖与dox联合暴露促成了最强的EF降低和衰老升高。这些发现强调了蔗糖摄入对蒽环类药物相关心脏损伤的贡献，并支持将膳食调控作为减轻长期心脏损害的潜在策略加以研究。
查看英文原文 English abstract
Anthracyclines such as doxorubicin (dox) are effective chemotherapeutic agents frequently used in adolescents and young adults (AYAs) with cancer but are associated with cardiotoxicity. Mitigation of cardiac late effects through modifiable behaviors has global and cost-effective benefits, but parameters influencing potential benefit remain unclear. Here, we investigated the impact of sucrose consumption on dox-induced cardiotoxicity and senescence in vivo. Male and female p16/3MR transgenic mice were provided normal (NSW, 0%) or high (HSW, 45%) sucrose water and treated with dox (2.5 mg/kg, tail vein ×4 doses). Cardiac function was assessed by echocardiography to measure ejection fraction (EF) and fractional shortening (FS). Cardiac miR-1a and miR-499 expression were quantified by qRT-PCR, and senescent cell accumulation was visualized in heart tissue by red fluorescent protein (RFP) signal. High sucrose intake worsened dox-associated reductions in ejection fraction, with the HSW + dox group showing the greatest functional decline, a pattern that was statistically significant at 4 weeks (p = 0.0187) and 6 weeks (p = 0.0353) post-treatment. Notably, high sucrose alone reduced EF relative to NSW controls, indicating diet-induced impairment of cardiac function. Dox treatment elevated biomarkers of myocardial stress (miR-1a and miR-499) in cardiac tissue, and high sucrose alone produced comparable upregulation. Senescence, as measured by RFP fluorescence, increased in both dox- and sucrose-exposed hearts. Interestingly, the HSW + dox group demonstrated the highest RFP signal, compared to both dox and diet controls, indicating a synergistic enhancement of senescence, suggesting that molecular senescence markers may capture early injury preceding functional decline. High dietary sucrose both amplifies and independently impairs cardiac function and increases senescence, with combined sucrose and dox exposure promoting the strongest EF reduction and senescence elevation. These findings underscore the contribution of sucrose consumption to anthracycline-associated cardiac injury and support the investigation of dietary modulation as a potential strategy to mitigate long-term cardiac damage.
利益披露 Disclosure
A. L. Poche, None..
H. Ma, None..
P. Jeyabal, None..
F. Wang, None..
E. Koutroumpakis, None..
E. S. Kleinerman, None..
J. Chandra, None.