Abstract P3006: Angiotensin-(1-7) Prevents Doxorubicin-Induced Aortic Dysfunction Through Anti-Fibrotic Mechanisms in Juvenile Male and Female Sprague Dawley Rats

Abstract

Doxorubicin (Dox) is an effective, anthracycline chemotherapeutic administered for a variety of malignancies, but clinical use of the drug is limited by a cumulative, dose-dependent cardiotoxicity. Thus, adjuvant therapies are needed to mitigate Dox-induced cardiovascular damage in cancer patients, especially in pediatric patients with decades of life ahead. Our group showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone with anti-cancer properties, improved vascular dysfunction in coronary vessels and cremaster muscle microvessels in Ang II-infused rats. In this study, juvenile male and female Sprague Dawley rats (n = 8-10) were administered a clinically equivalent dose of Dox (21-24 mg/kg) over 6 weeks, in the presence or absence of Ang-(1-7) [24 μg/kg/h]. Aortic function was measured using echocardiography. In both sexes, Ang-(1-7) blocked the Dox-mediated increase in pulse wave velocity (PWV), a measure of arterial stiffness (75% in males and 179% in females, p<0.05 and p<0.001). Dox decreased aortic lumen diameter (by 18%, p<0.01) and increased wall thickness at systole (p<0.01) in males, which was attenuated by Ang-(1-7). In male but not female aortas, Dox increased media hypertrophy by 16% (p<0.01) and reduced elastin content by 17% compared to control rats (p<0.001), changes prevented by Ang-(1-7). Conversely, collagen deposition was increased 2.5-fold in the aortic arches of female rats treated with Dox (p<0.001), which was blocked by Ang-(1-7). Dox increased nuclear ERK1/2 by 2-fold in the aortic media of male rats (p<0.01) and Ang-(1-7) significantly attenuated nuclear ERK1/2 localization. In contrast, neither Dox nor Ang-(1-7) changed total or nuclear ERK1/2 in the aortic arches of female rats. Dox increased nuclear pSMAD2 4-fold in males (p<0.05) and 3-fold in females (p<0.05); prophylactic treatment with Ang-(1-7) reduced the Dox-induced increases in nuclear pSMAD2 while the heptapeptide hormone had no effect alone. These results demonstrate that Ang-(1-7) prevented Dox-induced aortic dysfunction in both sexes, albeit through different mechanisms, suggesting that treatment with Ang-(1-7) may serve as an effective adjuvant to improve Dox-induced vascular dysfunction in pediatric patients.