Characterization of a murine model of endothelial dysfunction induced by chronic intraperitoneal administration of angiotensin II

Abstract

Endothelial dysfunction (ED) is a key factor for the development of cardiovascular diseases. Due to its chronic, life-threatening nature, ED only can be studied experimentally in animal models. Therefore, this work was aimed to characterize a murine model of ED induced by a daily intraperitoneal administration of angiotensin II (AGII) for 10 weeks. Oxidative stress, inflammation, vascular remodeling, hypertension, and damage to various target organs were evaluated in treated animals. The results indicated that a chronic intraperitoneal administration of AGII increases the production of systemic soluble VCAM, ROS and ICAM-1 expression, and the production of TNFα, IL1β, IL17A, IL4, TGFβ, and IL10 in the kidney, as well as blood pressure levels; it also promotes vascular remodeling and induces non-alcoholic fatty liver disease, glomerulosclerosis, and proliferative retinopathy. Therefore, the model herein proposed can be a representative model for ED; additionally, it is easy to implement, safe, rapid, and inexpensive.

Hepatoprotective effect of hydroalcoholic extract from root of Sechium edule (Jacq.) Sw. over hepatic injury induced by chronic application of angiotensin II

“…In this work, we demonstrated the efficacy of the hydroalcoholic extract of S. edule roots in controlling the pathological conditions that often accompany NASH, such as hepatomegaly, hypertriglyceridemia, and adipose tissue enlargement, effectively controlling triglyceride accumulation in the liver, necrosis, inflammation, and fibrosis. This study confirms the previously reported association between the chronic administration of ANGII by the i. p. route and the development of metabolic alterations in the liver (Trejo-Moreno et al, 2018, Trejo-Moreno et al, 2021.…”

“…Coumaric acid, the second most abundant molecule in rSe-HA (Figure 1A), could provide the extract with antioxidant properties along with cinnamic acid (Shen et al, 2019;Anlar, 2020); the latter compound has also been shown to exert anti-inflammatory effects (Karatas et al, 2020). Both major components of rSe-HA could explain the efficacy of the extract in controlling NASH-like liver damage, as ANGII is known to induce oxidative stress and an inflammatory state (Wei et al, 2008;Trejo-Moreno et al, 2021). It should be noted that the dose used in this work is lower than those administered in studies conducted with aerial parts of the plant; previous studies used leaf or stem extracts at 0.1-0.5%, which is approximately equivalent to 1-5 g/kg (Yang et al, 2015) or 100-200 mg/kg of fruit extracts (Firdous et al, 2012); this could suggest a greater potency in root-derived extracts.…”

“…ANGII is a pleiotropic hormone. Although its effects are different depending on the target cell (Patel et al, 2017), it generally induces oxidative stress and inflammation (Wei et al, 2008;Trejo-Moreno et al, 2021) and plays a role in the development of metabolic diseases such as NASH (Wei et al, 2008;Rolo et al, 2012). Our results indicate that ANGII induced, on one hand, adipocyte hyperplasia and hypertrophy and the weight of the tissue and directly impacting on total weight gain in mice (Figures 4A,B); on the other hand, it also induced hepatic steatosis and hepatomegaly (Figures 2A,B,D,H).…”

“…However, the root had not been studied as a therapeutic tool in hepatic diseases. In a previous work by our research group, an acetone fraction of S. edule root (rSe-FA) was found to be effective in controlling ED induced in mice by chronic administration of a sub-effective dose of ANGII; in that study, ANGII was found to induce morphological changes in the liver similar to those of NASH (Trejo-Moreno et al, 2021), and that administration of this fraction prevented such damage (Trejo-Moreno et al, 2018). Moreover, the fraction was rich in cinnamic and coumaric acids, whose antioxidant (Shen et al, 2019;Anlar, 2020) and anti-inflammatory properties (Karatas et al, 2020)…”

“…One Vehicle group was administered water only. The remaining three groups were treated with ANGII (Sigma, St. Louis, MO, United States) i. p, 0.01 μg/kg/day (ANGII) (Trejo-Moreno et al, 2021), for 11 weeks, either alone or coadministered p. o. with Losartan (LOS) (Cozaar ® , Merck Sharp & Dohme, Kenilworth, NJ, United States) at a dose of 10 mg/kg diluted in 0.2% carboxymethylcellulose (CMC, Maquimex, Mexico) (Bastaki, et al, 2018) or rSe-HA diluted in water, at a dose of 11 mg/kg, for 11 weeks. Both treatment time and the dose administered were based on data previously reported by Trejo-Moreno et al (2018).…”