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

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.

Diminazene aceturate exacerbates renal fibrosis after unilateral ureteral obstruction in female mice

“…As we had determined that DIZE aggravated the infiltration of total macrophages after UUO ( Fig. 5 ), and because it was recently suggested that DIZE shifts macrophage polarization toward the profibrotic M2 phenotype in atherosclerotic lesions [ 26 ], we evaluated M2 macrophage accumulation by IHC staining. In addition, we measured levels of cytokines and chemokines involved in M2 macrophage survival and polarization.…”

COVID-19 and Diarylamidines: The Parasitic Connection

“…The modulation of LPS activity via arylamidines and the potential implications regarding potential treatments of numerous diseases associated with aberrant immune activation and coagulation have led to a flurry of animal model studies, including (i) amelioration of neurological pathologies (Alzheimer’s) [ 55 ]; (ii) cardiac (atherosclerotic plaque stabilization, cardiac fibrosis) [ 56 , 57 , 58 ]; (iii) pulmonary (hypertension) [ 59 ]; (iv) liver (injury and biliary fibrosis) [ 60 ]; (v) diabetic (type 1) [ 61 ]; (vi) acute radiation exposure/damaged tissue (ARE) [ 62 ] ( Table 2 ).…”

Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19

“…Additionally, Mas-receptor deficiency augmented AngII-induced atherosclerosis and plaque rupture through mechanisms involving increased oxidative stress, inflammation, and apoptosis [ 184 ]. All of these complications were abolished by overexpression of ACE2 [ 54 , 186 , 187 , 188 , 189 ] and treatment with ACE2 activator (DIZE) [ 190 , 191 ] or subcutaneous Ang(1-7) [ 192 ]. Taken together, there is evidence regarding components of ACE2-Ang(1-7)-Mas axis involvement in CAD devolvement and progression; however, to further elucidate the therapeutic potential of modulation of this axis will require utilization of more selective tools to separate the upstream RAS effects provided by ACE inhibitors or AT1 blockers in general CAD therapy.…”