Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice

Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1-7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Aug 11 and forms Ang-(1-7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shear stress (SS) modifier device. The animals were treated with diminazene (15 mg/kg/day) or vehicle. ACE2 was strongly expressed in the aortic root and low SS-induced carotid plaques, but poorly expressed in the oscillatory SS-induced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorated the composition of aortic root and low SS-induced carotid plaques by increasing collagen content and decreasing both MMP-9 expression and macrophage infiltration. Interestingly, these beneficial effects were not observed in the oscillatory SS-induced plaque. Additionally, diminazene treatment decreased intraplaque ICAM-1 and VCAM-1 expression, circulating cytokine and chemokine levels and serum triglycerides. In summary, ACE2 was distinctively expressed in atherosclerotic plaques, which depends on the local pattern of shear stress. Moreover, diminazene treatment enhances the stability of atherosclerotic plaques. (C) 2015 Elsevier Inc. All rights reserved.

Role of Renin-Angiotensin System in Inflammation, Immunity and Aging

Luciano Dos Santos Aggum Capettini, Rafaela Fernandes Da Silva, Nikolaos Stergiopulos

Recent data support the idea that the effects of RAS are not restricted to the cardiovascular and renal systems. Importantly, RAS modulates free radical production and the cellular synthesis of several molecules such as cytokines, chemokines and transcription factors. These functions reflect directly the RAS ability to modulate the cell growth, senescence and migration. Activation of the classic RAS, ACE/Ang II/AT(1)R, has been strictly related to down regulation of pro-survival genes (Nampt and Sirt3), increase in ROS production and pro-inflammatory cytokines and chemokines release, leading to cell senescence, inflammation and development of autoimmune dysfunctions. However, the new view of RAS, points to the ACE2/Ang-(1-7)/Mas receptor axis as a counter-regulator of the effects of the classic Ang II-mediated effects. This new pathway is not totally elucidated. However, some studies suggest an important role of this novel axis in the control of cytokines release as well as cell migration and synthesis, preventing extra-cellular matrix deposition and cell apoptosis. Classic RAS blockers have been proposed as anti-inflammatory and immunomodulatory agents and some studies suggest a new potential application of RAS blockers in autoimmune diseases. The aim of the present review is to update the novel roles of classical and new RAS components and their possible implication during the physiological aging, in the immune system and inflammation.

Bentham Science Publishers2012

Treatment with Angiotensin-(1-7) reduces inflammation in carotid atherosclerotic plaques

Luciano Dos Santos Aggum Capettini, Rafaela Fernandes Da Silva, Katia Galan, Fabiana Pereira Da Costa Fraga, Nikolaos Stergiopulos

Angiotensin (Ang)-(1-7), acting through the receptor Mas, has athero-protective effects; however, its role on plaque vulnerability has been poorly studied. Here, we investigated the expression of the renin-angiotensin system (RAS) components in stable and unstable human carotid plaques. In addition, we evaluated the effects of the chronic treatment with an oral formulation of Ang-(1-7) in a mouse model of shear stress-determined carotid atherosclerotic plaque. Upstream and downstream regions of internal carotid plaques were obtained from a recently published cohort of patients asymptomatic or symptomatic for ischaemic stroke. Angiotensinogen and renin genes were strongly expressed in the entire cohort, indicating an intense intraplaque modulation of the RAS. Intraplaque expression of the Mas receptor I mRNA was increased in the downstream portion of asymptomatic patients as compared to corresponding region in symptomatic patients. Conversely, AT1 receptor gene expression was not modified between asymptomatic and symptomatic patients. Treatment with Ang-(1-7) in ApoE(-/-) mice was associated with increased intraplaque collagen content in the aortic root and low shear stress-induced carotid plaques, and a decreased MMP-9 content and neutrophil and macrophage infiltration. These beneficial effects were not observed in the oscillatory shear stress-induced plaque. In vitro incubation with Ang-(1-7) did not affect ICAM-1 expression and apoptosis on cultured endothelial cells. In conclusion, Mas receptor is up regulated in the downstream portions of human stable carotid plaques as compared to unstable lesions. Treatment with the oral formulation of Ang-(1-7) enhances a more stable phenotype in atherosclerotic plaques, depending on the local pattern of shear stress forces.

Schattauer2014

Update on the role of angiotensin in the pathophysiology of coronary atherothrombosis

Rodrigo Araujo Fraga Da Silva, Nikolaos Stergiopulos

BackgroundCoronary atherothrombosis due to atherosclerotic plaque rupture or erosion is frequently associated with acute coronary syndromes (ACS). Significant efforts have been made to elucidate the pathophysiological mechanisms underlying acute coronary events. Materials and methodsThis narrative review is based on the material searched for and obtained via PubMed up to August 2014. The search terms we used were as follows: angiotensin, acute coronary syndromes, acute myocardial infarction' in combination with atherosclerosis, vulnerability, clinical trial, ACE inhibitors, inflammation'. ResultsAmong several regulatory components, the renin-angiotensin system (RAS) was shown as a key pathway modulating coronary atherosclerotic plaque vulnerability. Indeed, these molecules are involved in all stages of atherogenesis. Classically, the RAS is composed by a series of enzymatic reactions leading to the angiotensin (Ang) II generation and activity. However, the knowledge of RAS has expanded and become more complex. The discovery of novel components and their functions has revealed additional pathways that contribute to or counterbalance the actions of Ang II. In this review, we discussed on recent findings concerning the role of different angiotensin peptides in the pathophysiology of ACS and coronary atherothrombosis, exploring the link between these molecules and atherosclerotic plaque vulnerability. ConclusionsTreatments selectively targeting angiotensins (including Mas and AT2 agonists, ACE2 recombinant, or Ang-(1-7) and almandine in oral formulations) have been tested in animal studies or in small human subgroups, expanding the perspective in the ACS prevention. These novel strategies, especially in the counter-regulatory axis ACE2/Ang-(1-7)/Mas, might be promising to reduce plaque vulnerability and inflammation.