Hypertension and Vascular Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Am J Physiol Heart Circ Physiol. 2020 Apr 1;318(4):H883-H894. doi: 10.1152/ajpheart.00224.2019. Epub 2020 Feb 21.
Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak () ( < 0.05) and early diastole mitral valve annulus peak velocity (; < 0.001) and increased ( < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1-7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 ( < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal ( < 0.001) and malondialdehyde ( < 0.001), markers of lipid peroxidation; Ang-(1-7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1-7) increased the antioxidant enzymes SOD1 (male: < 0.05; female: < 0.01) and catalase ( < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1-7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity. Ang-(1-7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.
多柔比星（Dox）是多种儿科恶性肿瘤的有效化疗药物。不幸的是，多柔比星的给药常常导致累积剂量依赖性的心脏毒性，表现为明显的氧化应激，导致心力衰竭。需要辅助治疗来减轻多柔比星的心脏毒性，提高癌症患儿的生活质量。血管紧张素-（1-7）[Ang-（1-7）]是一种具有心脏保护作用的内源性激素。本研究探讨了在雄性和雌性幼年大鼠中，辅助 Ang-（1-7）是否能减轻多柔比星引起的心脏毒性。多柔比星显著降低了体重，而添加 Ang-（1-7）没有影响。然而，辅助 Ang-（1-7）预防了多柔比星介导的舒张功能障碍，包括通过降低早期舒张二尖瓣血流速度峰值（ ）（ < 0.05）和早期舒张二尖瓣瓣环峰值速度（ ）（ < 0.001）来衡量的被动充盈减少的标志物，以及舒张功能障碍的超声心动图测量值（ < 0.001）。由于多柔比星治疗会增加活性氧（ROS），因此研究了 Ang-（1-7）对产生或减少 ROS 的氧化副产物和酶的影响。在雄性和雌性幼年大鼠的心脏中，多柔比星增加了 NADPH 氧化酶 4（ < 0.05），这是一种主要的心血管 NADPH 氧化酶同工酶，可产生 ROS，以及 4-羟基壬烯醛（ < 0.001）和丙二醛（ < 0.001），这是脂质过氧化的标志物；Ang-（1-7）预防了多柔比星的这些作用。多柔比星和 Ang-（1-7）联合治疗增加了抗氧化酶 SOD1（雄性： < 0.05；雌性： < 0.01）和过氧化氢酶（ < 0.05），这可能有助于减少 ROS。这些结果表明，Ang-（1-7）可预防舒张功能障碍，并与 ROS 减少相关，表明该七肽激素可能作为一种有效的辅助药物，以改善多柔比星引起的心脏毒性。Ang-（1-7）是一种临床安全的肽类激素，具有心脏保护和抗肿瘤作用，可作为辅助治疗药物，以改善癌症治疗，并减轻癌症患儿多柔比星相关的长期心脏毒性。
