Angiotensin-converting enzyme 2 overexpression protects against doxorubicin-induced cardiomyopathy by multiple mechanisms in rats

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.

AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension

“…We found little change in p-AMPK/AMPK in the lung tissue from both ACE2 S680D knock-in and ACE2 2/2 mice (data not shown). Thus, the putative feedback loop regulation of AMPK-ACE2 reported by Ma and colleagues was not apparent in our experimental system (53).…”

AMPK: a balancer of the renin–angiotensin system

“…As a core enzyme in the metabolism of AngII, ACE2 directly regulates the levels of AngII and Ang(1-7). ACE2 is accepted as an Ang(1-7) marker and considered to be a feasible therapeutic target of the RAS [26,122]. Based on current researches, ACE2 and AMPK have closed relations.…”

“…In Na et al's [144] study, vinegar and acetic acid decreased serum renin and ACE activities, AngII and aldosterone concentration in SHRs, simultaneously, elevated AMP/ATP ratios and the phosphorylation of AMPK, PPARγ, co-activator-1α (PGC-1α) [144]. In 2017, one study demonstrated that ACE2 overexpression down-regulated the mortality of rats with doxorubicin-induced cardiomyopathy [122]. Its mechanism may involve activation of the AMPK and PI3K-AKT pathways, inhibition of ERK pathway and TGF-β1 expression [122].…”

“…In 2017, one study demonstrated that ACE2 overexpression down-regulated the mortality of rats with doxorubicin-induced cardiomyopathy [122]. Its mechanism may involve activation of the AMPK and PI3K-AKT pathways, inhibition of ERK pathway and TGF-β1 expression [122]. At the same time, ACE2 overexpression can reduce ACE expression, myocardial AngII levels, and increase myocardial Ang (1-7) degrees.…”

Downregulation of miR-3568 Protects Against Ischemia/Reperfusion-Induced Cardiac Dysfunction in Rats and Apoptosis in H9C2 Cardiomyocytes Through Targeting TRIM62

“…For direct cardiac function evaluation, hemodynamic measurements were recorded and calculated with a pressure volume catheter (SPR-838, Millar Instruments, Houston, TX, USA) using the Millar pressure-volume system (MPVS-300, Millar Instruments) as previously described (Malka et al, 2016). Echocardiographic measurements were performed using a 7.5-MHz phased-array transducer connected to a sector scanner (SONOS 7500, Philips Medical Systems, Andover, MA) as previously described (Ma et al, 2017). Echocardiography cines were obtained according to the American Society of Echocardiography guidelines (Arias et al, 2013).…”