**Involvement of the Renin‐Angiotensin System in Atherosclerosis**

Ana Kolakovic, Maja Zivkovic and Aleksandra Stankovic

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67137

### Abstract

The renin-angiotensin system (RAS) is a well known for its role in the regulation of the blood pressure (BP). Angiotensin II (Ang II), the main mediator of the RAS, may act either, as a systemic molecule or a locally produced factor. Within the vessel wall it has significant proinflammatory role by inducing the oxidative stress, secretion of inflammatory cytokines and adhesion molecules. Ang II could trigger proliferation of vascular smooth muscle cells (VSMC) and its migration to the outer layer of the vessel wall. It could induce the release of matrix metalloproteinase (MMPs), from human VSMC and thus increase susceptibility to rupture of atherosclerotic lesions. Binding of Ang II to AT1R/AT2R could have opposing actions in vascular injury. The ACE2/Ang (1-7)/Mas axis of the RAS also opposes the unfavourable actions of ACE/Ang II/ATR1 axis. Inhibition of RAS could reduce inflammation-associated processes in vasculature, independently of lowering BP. RAS is significantly modulated by the genes coding for this system. Certain genetic variants (SNPs) in the RAS genes have been denoted as the functional ones and have been associated with hypertension, cardiovascular phenotypes and atherosclerosis. Also, the genetic components of the RAS interfere with the regulators of gene expression by microRNAs (miRs).

Keywords: renin-angiotensin system, atherosclerosis, genetic variant, micro RNA gene expression

### 1. Introduction

### 1.1. Short overview of the RAS

The renin-angiotensin system (RAS) is a cascade well known for its primary role in the regulation of blood pressure (BP) and sodium homeostasis. It has a significant role in regulating fluid and electrolyte balance by exerting its actions on the heart, blood vessels and kidneys.

The circulating RAS comprises liver-secreted angiotensinogen (AGT) that is enzymatically converted into angiotensin I (Ang I) in the bloodstream by kidney-derived renin. In the next step, Ang I is being converted by angiotensin-converting enzyme (ACE) to form Ang II. Ang II is the main effector in this system that acts either as a systemic molecule or as a locally produced factor.

The RAS is probably one of the most investigated biological systems over past 30 years. Given its pleiotropic biological effects, it is expected. Its complexity underlies the fact that research involving RAS molecules and actions in health and disease is still very active and intriguing. In the past decade, a substantial expansion of our knowledge of the RAS was emerged. It is verified by newly discovered components. One of them is a homologue of ACE, angiotensinconverting enzyme 2 (ACE2), which exerts a role as a negative regulator of the RAS [1] by cleaving Ang II to Ang-(1–7) [2, 3]. Namely, Santos et al. demonstrated that Ang-(1-7) is the ligand for the G-protein-coupled receptor Mas, and that the ACE2–Ang-(1–7)–Mas axis is the counter-regulating of the actions of classical RAS [4, 5]. Also, a variety of biologically active peptides, novel components of the RAS have been found recently: proangiotensin-12 (angiotensin-(1–12)) [6], angiotensin A (Ang A) [7, 8] and alamandine [9, 10].

### 1.2. Tissue and intracellular RAS

Our knowledge of the RAS has undergone substantial revision in the past few years. The existence of local (tissue) RAS systems that are independent of those stimulated by the classical RAS made it evident that the RAS is more complex than originally thought [11]. In that way, RAS is experienced substantial conceptual changes. Local (tissue) RAS represents tissue-based formation of angiotensin peptides that operate separately from the circulating RAS [12]. Tissue RAS systems are located in all major organs, including brain, heart, large blood vessels, adrenals and the kidneys [13]. Local RAS systems exert various actions depending on the type of cells involved and play crucial role in the maintenance of cellular homeostasis.

In order to identify a tissue-specific RAS at least one of the following criteria have to be fulfil [14]: (1) mRNAs for all components required for biosynthesis of a biologically active Ang II are present, (2) a biologically active angiotensin peptide is synthesized, (3) receptors for the biologically active angiotensin peptide are present, (4) the biologically active angiotensin peptide in the tissue is regulated, independently of the circulating RAS and (5) reduction or elimination of the action of the angiotensin peptide produces a physiological response.

There are other components of local RAS that are contributing to tissue-specific mechanisms of angiotensin peptide formation. They are participating in the progression of disease, or contrary, in mechanisms that protect from tissue injury [12]. These components include the (pro) renin receptor [15, 16], renin-independent mechanisms of Ang peptide generation from Ang- (1–12) [17, 18], intracellular RAS [19], previously mentioned ACE2/Ang-(1–7)/Mas receptor pathway [20] and they all may possess therapeutic potential.

Although different concepts of local RAS have been described, its key characteristic is a synthesis of AGT and enzymes, such as renin, that cleaves AGT to produce Ang I independently of the circulating RAS [12, 21, 22]. The presence of ACE, Ang II type 1 (AT1R) and type 2 (AT2R) receptors and Ang II in different cells supports the concept of local RAS [23]. The local RAS seems to be regulated independently from the circulating system in a specific manner depending on the cell type and extracellular stimulus [24]. Despite that it can interact with the circulating system and complement it.

Some of the attempts to define local RAS that are independent of the circulating RAS were made in animal models [12]. One of the approaches to studying the functional importance of locally synthesized RAS components is to demonstrate their targeted overexpression or deletion in specific tissues. The evidence shows that in most tissues, local RAS enhances the actions of circulating Ang II, which has important implications for the pathophysiology of cardiovascular diseases.

In addition to classical and local tissue RAS, there is an intracellular RAS. This system is characterized by the presence of a functionally active RAS within the cells that can intracellularly synthesize Ang II [19, 25]. This means that Ang II is involved not only in an endocrine but also is a paracrine and an intracrine signaling system within tissues [26]. For example, intracellular delivery of Ang II leads to increase in intracellular calcium, growth of vascular smooth muscle cells (VSMCs) and regulation of muscle tone [27, 28]. This suggests that the intracellular Ang II has different functions compared to extracellular Ang II.
