Diminazene Aceturate Stabilizes Atherosclerotic Plaque and Attenuates Hepatic Steatosis in apoE-Knockout Mice by Influencing Macrophages Polarization and Taurine Biosynthesis.

Rafał Olszanecki,Jacek Jawień,Justyna Totoń-Żurańska,Beata Bujak-Giżycka,Magdalena Łomnicka,Magdalena Białas,Anna Kiepura,Kamila Stachyra,Anna Wiśniewska,Maciej Suski,Katarzyna Kuś,Aneta Stachowicz

doi:10.3390/ijms22115861

Diminazene Aceturate Stabilizes Atherosclerotic Plaque and Attenuates Hepatic Steatosis in apoE-Knockout Mice by Influencing Macrophages Polarization and Taurine Biosynthesis.

Rafał Olszanecki, Jacek Jawień + Show 10 more

Open Access

https://doi.org/10.3390/ijms22115861

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Abstract

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin–angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1–7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1–7) and thus favors Ang-(1–7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE−/− mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE−/− mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE−/− mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.

Highlights

Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are leading causes of morbidity and mortality in the Western countries [1]
We found that Angiotensin-converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE), stabilized atherosclerotic plaque and attenuated hepatic steatosis in apoE−/− mice by influencing macrophages polarization and taurine biosynthesis
The animals were divided into two groups: female apoE−/− mice on high-fat diet (n = 11) and female apoE−/− mice on an HFD treated with diminazene aceturate (DIZE) (n = 11)

Summary

Introduction

Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are leading causes of morbidity and mortality in the Western countries [1]. Atherosclerosis, a multifactorial inflammatory illness of arteries, is characterized by a lipid-rich necrotic core and a ruptureprone fibrous cap. The rupture of the atherosclerotic plaque can cause life-threatening complications: coronary artery disease, stroke, peripheral artery disease, and myocardial infarction [2]. Endothelial activation is an initial step of atherogenesis that promotes the accumulation of oxidized low-density lipoproteins (ox-LDL), monocytes, and other inflammatory cells in the subendothelial space. The engulfment of ox-LDL by macrophages, exacerbation of inflammation, migration and activation of vascular smooth muscle cells (VSMC), and apoptosis of macrophages and VSMC occurs [3,4]. Mounting evidence indicates that NAFLD, which is manifested by triglyceride accumulation

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