Table_1_Divergent Cardiac Effects of Angiotensin II and Isoproterenol Following Juvenile Exposure to Doxorubicin.DOCX

Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. It is still not known how juvenile DOX-induced latent cardiotoxicity would predispose the heart to pathologic stimuli that do not cause hypertension. Our main objective is to determine the cardiac effects of ANGII (a hypertensive pathologic stimulus) and isoproterenol (ISO, a non-hypertensive pathologic stimulus) in adult mice pre-exposed to DOX as juveniles. Five-week-old male C57BL/6N mice were administered DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were administered either ANGII (1.4 mg/kg/day) or ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers, ANP and BNP. ANGII, but not ISO, worsened cardiac function and exacerbated cardiac fibrosis in DOX-exposed mice as measured by echocardiography and histopathology, respectively. The adverse cardiac remodeling in the DOX/ANGII group was associated with a marked upregulation in several inflammatory and fibrotic markers and altered expression of Ace, a critical enzyme in the RAAS. In conclusion, juvenile exposure to DOX causes latent cardiotoxicity that predisposes the heart to a hypertensive pathologic stimulus (ANGII) more than a non-hypertensive stimulus (ISO), mirroring the clinical scenario of worse cardiovascular outcome in hypertensive childhood cancer survivors.

高血压是儿童癌症幸存者接受多柔比星（DOX）治疗后发生心力衰竭的最重要风险因素。我们先前开发了一种青少年多柔比星诱导的潜在心脏毒性双重打击小鼠模型，该模型在成年后由血管紧张素II（ANGII）诱导的高血压作用下加剧。目前尚不清楚青少年多柔比星诱导的潜在心脏毒性如何使心脏易受非高血压病理刺激的影响。我们的主要目标是确定血管紧张素II（一种高血压病理刺激）和异丙肾上腺素（ISO，一种非高血压病理刺激）在成年小鼠中预先暴露于DOX（作为青少年）对心脏的影响。五周大的雄性C57BL/6N小鼠接受DOX（每周4 mg/kg）或生理盐水处理3周，然后恢复5周。此后，小鼠分别接受ANGII（每天1.4 mg/kg）或ISO（每天10 mg/kg）处理14天。青少年期暴露于DOX消除了对ANGII和ISO的肥大反应，但未能纠正ANGII和ISO诱导的肥大标志物ANP和Bnp的上调。血管紧张素II，而非ISO，通过超声心动图和病理学分别评估，恶化了DOX暴露小鼠的心脏功能并加剧了心脏纤维化。DOX/ANGII组的不良心脏重塑与多种炎症和纤维化标志物的显著上调以及RAAS关键酶Ace的表达改变有关。总之，青少年期暴露于DOX会导致潜在的心脏毒性，使心脏对高血压病理刺激（ANGII）比对非高血压刺激（ISO）更为易感，这与高血压儿童癌症幸存者临床情况中更差的心血管结局相呼应。