International Journal of Molecular Sciences Review Renin-Angiotensin System in Pathogenesis of Atherosclerosis and Treatment of CVD Anastasia V. Poznyak 1,* , Dwaipayan Bharadwaj 2,3, Gauri Prasad 3, Andrey V. Grechko 4, Margarita A. Sazonova 5 and Alexander N. Orekhov 1,5,6,* 1 Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia 2 Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi 110067, India; [email protected] 3 Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India; [email protected] 4 Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 14-3 Solyanka Street, 109240 Moscow, Russia; [email protected] 5 Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; [email protected] 6 Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia * Correspondence: [email protected] (A.V.P.); [email protected] (A.N.O.) Abstract: Atherosclerosis has complex pathogenesis, which involves at least three serious aspects: inflammation, lipid metabolism alterations, and endothelial injury. There are no effective treatment options, as well as preventive measures for atherosclerosis. However, this disease has various severe complications, the most severe of which is cardiovascular disease (CVD). It is important to note, that CVD is among the leading causes of death worldwide. The renin–angiotensin–aldosterone system (RAAS) is an important part of inflammatory response regulation. This system contributes to Citation: Poznyak, A.V.; Bharadwaj, the recruitment of inflammatory cells to the injured site and stimulates the production of various D.; Prasad, G.; Grechko, A.V.; cytokines, such as IL-6, TNF-a, and COX-2. There is also an association between RAAS and oxidative Sazonova, M.A.; Orekhov, A.N. Renin-Angiotensin System in stress, which is also an important player in atherogenesis. Angiotensin-II induces plaque formation at Pathogenesis of Atherosclerosis and early stages, and this is one of the most crucial impacts on atherogenesis from the RAAS. Importantly, Treatment of CVD. Int. J. Mol. Sci. while stimulating the production of ROS, Angiotensin-II at the same time decreases the generation 2021, 22, 6702. https://doi.org/ of NO. The endothelium is known as a major contributor to vascular function. Oxidative stress is 10.3390/ijms22136702 the main trigger of endothelial dysfunction, and, once again, links RAAS to the pathogenesis of atherosclerosis. All these implications of RAAS in atherogenesis lead to an explicable conclusion Academic Editor: Manfredi Rizzo that elements of RAAS can be promising targets for atherosclerosis treatment. In this review, we also summarize the data on treatment approaches involving cytokine targeting in CVD, which can Received: 27 May 2021 contribute to a better understanding of atherogenesis and even its prevention. Accepted: 18 June 2021 Published: 22 June 2021 Keywords: atherosclerosis; CVD; RAAS; renin–angiotensin–aldosterone system Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Atherosclerosis is a serious health problem due to its relation to cardiovascular disease, which is one of the leading causes of death around the globe. Atherogenesis is based on three cornerstones: lipid metabolism alteration, inflammation, and endothelial injury. Endothelial injury acts as an initial trigger causing the accumulation and infiltration Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. of the multiple-modified low-density lipoprotein particles in the subendothelial space [1]. This article is an open access article Modified LDL stimulates the production of vascular cell adhesion molecules, such distributed under the terms and as VCAM-1, P and E- selectins on the endothelial cells, which results in the recruitment conditions of the Creative Commons of leukocytes into subendothelial space. Then, inflammatory cells migrate into the in- Attribution (CC BY) license (https:// tima [2]. This process is mediated by the chemoattractant proteins, among which are creativecommons.org/licenses/by/ MCP-1(monocyte chemoattractant proteins), and others. Macrophages, after the trans- 4.0/). formation from monocytes, express SRA, CD36, LOX-1, and other scavenger receptors, Int. J. Mol. Sci. 2021, 22, 6702. https://doi.org/10.3390/ijms22136702 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 6702 2 of 12 Int. J. Mol. Sci. 2021, 22, 6702 2 of 12 from monocytes, express SRA, CD36, LOX-1, and other scavenger receptors, which act throughwhich actmodified through LDL modified internalization. LDL internalization. Such cells with Such lipid cells contents with lipid are contentscalled foam are cells. called Itfoam is important cells. It isto importantnote that cells to note of other that cells types, of including other types, pericyte including-like pericyte-like cells, can also cells, trans- can formalso into transform foam cells. into foamFoam cells.cell emergence Foam cell is emergence an initial isstage an initialof atherosclerotic stage of atherosclerotic lesion for- mation.lesion formation.At this stage, At mast this stage, cells and mast foam cells cells and al foamong cellswith alongT-lymphocytes, with T-lymphocytes, that migrated that tomigrated the intima, to therelease intima, various release cytokines various stimulating cytokines stimulatinginflammation inflammation and production and of produc- reac- tivetion oxygen of reactive species oxygen (ROS) species [3,4]. Growth (ROS)[ factors3,4]. Growth released factors by these released cells as by well these as cells ROS as stim- well ulateas ROS smooth stimulate muscle smooth cell migration muscle celland migrationcollagen deposition and collagen leading deposition to the development leading to the ofdevelopment an atheromatous of an plaque atheromatous [5]. plaque [5]. ROSROS acts acts as as a atrigger trigger of of scavenger scavenger receptors’ receptors’ expression expression in in smooth smooth muscle muscle cells cells and and alsoalso induces induces their their transformation transformation into into foam foam cells. cells. Another Another role role of of ROS ROS in in atherogenesis atherogenesis consisconsiststs of of stimulation stimulation of of matrix matrix metalloproteinases metalloproteinases (MMPs) (MMPs) release, release, which which degrades degrades the the fibrousfibrous wall wall of of the the atheromatous atheromatous plaque plaque and and basement basement membrane membrane of of the the endothelial endothelial cells. cells. This,This, in in turn, turn, results results in in physical physical disruption disruption of of the the plaque, plaque, which which can can happen happen by by super superficialficial erosionerosion of of the the endothelial endothelial cells cells due due to to damage damage of of their their basement basement membrane, membrane, disruption disruption of of micromicro-vessels-vessels in in the the plaque, plaque, causing causing micro micro-hemorrhage/thrombosis,-hemorrhage/thrombosis, or or disruption disruption of of the the fibrousfibrous cap cap exposing exposing the the pro pro-thrombogenic-thrombogenic content ofof thethe plaque.plaque. SuchSuch damage damage can can lead lead to toa a sudden sudden expansion expansion of of lesions lesions and and can can promote promote arterial arterial thrombosis thrombosis [6 [].6]. 2.2. RAAS RAAS System System:: Inflammation Inflammation TheThe scheme scheme of of the the renin renin–angiotensin–aldosterone–angiotensin–aldosterone system system is is provided provided in in Figure Figure 1.1. FigureFigure 1. 1. ReninRenin cleaves cleaves angiotensinogen angiotensinogen into into 10 10 peptides peptides (Angiotensin (Angiotensin I). I). With With the the help help of of the the angiotensin angiotensin-converting-converting enzymeenzyme (ACE), (ACE), Angiotensin Angiotensin-I-I can can be further cleaved toto Angiotensin-II.Angiotensin-II. Then, Then, Angiotensin-I Angiotensin- isI is converted converted to to Angiotensin-1–9, Angiotensin- 1–and9, and Angiotensin-II—to Angiotensin-II— Angiotensin-1–7to Angiotensin-1 by–7 ACE2.by ACE2. Then, Then, Angiotensin-II Angiotensin is-II converted is converted into into Angiotensin-III. Angiotensin-III. Angiotensin-II Angioten- sinacts-II onacts Angiotensin on Angiotensin II receptor II receptor 1 (AT1R) 1 (AT1R) and AT2R.and AT2R. TheThe renin renin–angiotensin–aldosterone–angiotensin–aldosterone system system (RAAS) (RAAS) is isa akey key player player in in inflammatory inflammatory responseresponse regulation. regulation. This This system system manages manages the the recruitment recruitment of of inflammatory inflammatory elemen elementsts to to thethe site site of of injury. injury. Moreover, Moreover, these these inflammatory inflammatory cells cells can, can, in in turn, turn, generate generate A Angiotensinngiotensin II,II, contributing contributing to to a alocal local RAAS RAAS stimulation, stimulation, which which maintains maintains the the inflammatory inflammatory cycle cycle [7 []7. ]. AngiotensinAngiotensin II II has has numerous numerous functions, functions, acting acting as as a alocal local biologically biologically active active mediator mediator with with directdirect effects effects on on vascular vascular smooth smooth muscle muscle cells cells (VSMCs) (VSMCs) and and endothelial