Abstract
Angiotensin-converting enzyme 2 (ACE2) is considered a potential therapeutic target of the renin-angiotensin system (RAS) for the treatment of cardiovascular diseases. We aimed to explore the effects of ACE2 overexpression on doxorubicin-induced cardiomyopathy in rats. Rats were randomly divided into treatment and control groups. The rats of treatment group were injected intraperitoneally with 6 doses of doxorubicin (2.5 mg/kg) within a period of two weeks. Two weeks after the initial injection of doxorubicin, these rats were randomly divided into Mock, Ad-EGFP, Ad-ACE2, and Cilazapril groups. The rats of Ad-EGFP and Ad-ACE2 groups received intramyocardial injection of Ad-EGFP and Ad-ACE2, respectively. The rats of Cilazapril group received cilazapril (10 mg/kg/day) via intragastric intubation. Apoptosis, inflammation, oxidative stress, cardiac function, the extent of myocardial fibrosis, and levels of ACE2, ACE, angiotensin II (AngII), and angiotensin (1–7) were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed not only reduced apoptosis, inflammatory response, oxidative stress, left ventricular (LV) volume, extent of myocardial fibrosis and mortality of rats, but also increased LV ejection fraction and ACE2 expression level compared with the Mock and Ad-EGFP groups. ACE2 overexpression was superior to cilazapril in improving doxorubicin-induced cardiomyopathy. The putative mechanisms may involve activation of the AMPK and PI3K-AKT pathways, inhibition of the ERK pathway, decrease of TGF-β1 expression, and interactions of shifting RAS components, such as decreased myocardium AngII levels, increased myocardium Ang (1–7) levels, and reduced ACE expression. Thus, ACE2 may be a novel therapeutic approach to prevent and treat doxorubicin-induced cardiomyopathy.
Highlights
Doxorubicin is a commonly used chemotherapeutic agent for the treatment of solid and haematologic tumors
TUNEL assay was performed and the results showed that radio of TUNEL positive cells were significantly decreased in the Ad-Angiotensin-converting enzyme 2 (ACE2) and Cilazapril groups compared with the Mock and Ad-EGFP groups, with no significant difference between the Mock and AdEGFP groups or between the Ad-ACE2 and Cilazapril groups (Figure 3A and 3B)
There were two key findings of the present study, the first was that ACE2 overexpression decreased apoptosis, inflammatory response, and oxidative stress in doxorubicin-induced cardiomyopathy
Summary
Doxorubicin is a commonly used chemotherapeutic agent for the treatment of solid and haematologic tumors. The mechanisms of doxorubicin-induced cardiomyopathy remain not fully elucidated. Several agents including anti-oxidants, angiotensinconverting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB) and dexrazoxan have been employed for the attenuation of doxorubicin-induced cardiomyopathic damage [8, 9]. All of these agents have not yet gained effective enough evidence to justify a routine use. The search for a safe and www.impactjournals.com/oncotarget effective therapeutic method of preventing doxorubicininduced cardiomyopathy remains an important issue in both cardiology and oncology
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