Article: Angiotensin-(1-7) reduces doxorubicin-induced aortic arch dysfunction in male and female juvenile Sprague Dawley rats through pleiotropic mechanisms
2022
Abstract: Doxorubicin (Dox), an effective chemotherapeutic, can cause cumulative dose-dependent cardiovascular toxicity, which may manifest as vascular dysfunction leading to long-term end-organ damage. Currently, there are no effective treatments to mitigate Dox- ... ...
| Abstract | Doxorubicin (Dox), an effective chemotherapeutic, can cause cumulative dose-dependent cardiovascular toxicity, which may manifest as vascular dysfunction leading to long-term end-organ damage. Currently, there are no effective treatments to mitigate Dox-induced vascular damage in cancer patients, particularly pediatric patients. We showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone, mitigated cardiac damage in Dox-treated juvenile rats. In this study assessing aortic stiffness, juvenile male and female rats were administered a clinically equivalent dose of Dox (21–24 mg/kg) over 6 weeks, in the presence and absence of Ang-(1-7) [24 µg/kg/h]. Aortic function was measured using echocardiography. Ang-(1-7) reduced the Dox-mediated increase in pulse wave velocity, a measure of arterial stiffness (males: p < 0.05; females: p < 0.001) as compared in control animals. Dox decreased aortic lumen diameter (p < 0.0001) and increased wall thickness (p < 0.01) in males, which was attenuated by Ang-(1-7). In male but not female aortic arches, Dox increased media hypertrophy (p < 0.05) and reduced elastin content (p < 0.001), which were prevented by Ang-(1-7). Conversely, Dox increased fibrosis (p < 0.0001) in juvenile female rats, which was reduced by Ang-(1-7). Adjunct Ang-(1-7) prevented the Dox-induced increase in total cell and nuclear pERK1/2 in the aortic intima and media of male rats and nuclear pSMAD2 in the intimal and medial regions of the aortic arches of both sexes. These results demonstrate that Ang-(1-7) attenuated Dox-induced aortic dysfunction in both sexes of juvenile rats, albeit through different mechanisms, suggesting that Ang-(1-7) may serve as an effective adjuvant to ameliorate cardiovascular and long-term end-organ damage in pediatric patients produced by anthracyclines. |
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| Keywords | adjuvants ; dose response ; doxorubicin ; drug therapy ; echocardiography ; elastin ; females ; fibrosis ; hypertrophy ; juveniles ; males ; peptides ; toxicity |
| Language | English |
| Dates of publication | 2022-06 |
| Publishing place | Elsevier Inc. |
| Document type | Article |
| ZDB-ID | 769028-9 |
| ISSN | 1873-5169 ; 0196-9781 |
| ISSN (online) | 1873-5169 |
| ISSN | 0196-9781 |
| DOI | 10.1016/j.peptides.2022.170784 |
| Database | NAL-Catalogue (AGRICOLA) |
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