Atherosclerosis

Risks, Mechanisms, and Therapies

Hong Wang, Cam Patterson, Hong Wang, Cam Patterson

• Publisher: Wiley-Blackwell
• Year: 2015
• ISBN:
  9781118828519
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Cell Biology
• Index: Biological Sciences

Comprehensive and in-depth in its coverage, Atherosclerosis: Cellular, Molecular & Biochemical Mechanism and Novel Therapy reviews the recent progress in atherosclerosis research and offers cutting edge perspectives from experts in the field. Written by an international team of authors including leading physician-scientists, research experts and physicians, chapters are divided into four major sections, covering risk factors, cellular and molecular mechanisms, biochemical mechanisms and novel and future therapeutics.

Atherosclerosis: Cellular, Molecular & Biochemical Mechanism and Novel Therapy analyses recent progress from both conceptual and technological perspectives, suggesting new directions for atherosclerosis research and treatment for a growing population of researchers and clinicians in cardiovascular and related fields.

Section III
Molecular Mechanisms

17
Mechanisms of the Renin Angiotensin System Influencing Atherosclerosis

Hong Lu and Alan Daugherty

Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA

Introduction

The existence of the renin angiotensin system (RAS) was initially discovered more than a century ago, and the major bioactive octapeptide, angiotensin II (AngII), has been recognized for over seven decades. During the past decade, studies on this angiotensin peptide and other classical components have led to new insights into the RAS. While AngII is a critical regulator for blood pressure and water/sodium homeostasis, many other important roles of AngII have also been determined. In addition, it is now acknowledged that the RAS is a complex system that involves a spectrum of bioactive angiotensin peptides, multiple receptors that use these angiotensin peptides as ligands, and diverse enzymes that have the ability to generate these peptides. In addition to AngII, three other angiotensin peptides, that is, AngIII, AngIV, and Ang(1–7) are also biologically active. While AT1 and AT2 receptors are well-recognized AngII-binding receptors, AngIII, a downstream peptide generated from AngII, also binds to these two receptors with lower affinity than AngII. Angiotensin-converting enzyme 2 (ACE2) converts AngII into Ang(1–7) as well as cleaves AngI into Ang(1–9). Although the biological effect of Ang(1–9) is unclear, a recent study has provided evidence that Ang(1–9) can bind AT2 receptors [1].

In addition to the growing array of bioactive peptides of the RAS, many components of this system have been detected in different organs, tissues, and cell types, thereby adding another layer of complexity to this intricate system. The elaborate link among components in the RAS also leads to an impediment in understanding the “Yin” and the “Yang” of this hormonal system in pathophysiological conditions such as atherosclerosis.

There is compelling evidence from animal studies that the RAS influences atherosclerosis. Chronic infusion of AngII into hypercholesterolemic mice accelerates atherosclerosis [2–4]. Conversely, blockade of AngII synthesis or action through pharmacological inhibition or genetic disruption of some of the RAS components prevents the development of atherosclerosis [5–12]. Despite lack of direct evidence from human studies, large-scale clinical trials have demonstrated that pharmacological inhibition of either ACE [13] or AT1 receptor [14] has beneficial effects on atherosclerosis-related morbidity and mortality. In the Heart Outcomes Prevention Evaluation (HOPE) population, high plasma renin activity has also been identified as an independent predictor of major vascular events and mortality, inferring this rate-limiting enzyme for AngII synthesis is important in the development of atherosclerosis [15].

We have recently summarized the literature regarding the effects of modulation of the RAS on development of atherosclerotic lesions [16]. In this chapter, we will focus on recent mechanistic studies in animal models.

The Renin Angiotensin Components Influence Atherosclerosis

Accumulating evidence that the RAS influences atherosclerosis is predominately from mouse studies. Genetic manipulation and pharmacological approaches have been the most powerful approaches to studying the contribution of the RAS to atherosclerosis. However, there are some limitations of both approaches. The use of genetically engineered mice with deletions of critical components of the RAS is confounded by the presence of severe renal impairment. This occurs in mice with deficiency of angiotensinogen, renin, and angiotnesin-converting enzyme (ACE) with a less-severe phenotype present in mice with deletions of AT1 receptor subtypes. The potential confounding feature of pharmacological approaches is that many of the drugs have properties beyond influences on RAS. Irrespective of these disadvantages, the combination of these two approaches has strongly enhanced our understanding on how the RAS influences atherosclerosis.

Bioactive Angiotensin Peptides

To study the effects of bioactive angiotensin peptides on atherosclerosis, one direct approach has been to infuse an angiotensin peptide into hypercholesterolemic mice. Among the four recognized bioactive angiotensin peptides, AngII has been studied extensively in mouse models, while there is scant information regarding roles of AngIII, AngIV, and Ang(1–7) in the development of atherosclerosis. Many research groups have consistently demonstrated that infusion of AngII accelerates atherosclerosis in hypercholesterolemic mice [2–4]. As discussed in our previous review [17], evidence from AngII-infusion studies implicates that the RAS contributes to atherosclerosis beyond its well-known effect on blood pressure regulation. One example is that low-dietary sodium (Na 0.01% weight/weight in diet) intake reduces systolic blood pressure, but activates the RAS and augments atherosclerosis compared with high-dietary sodium intake (Na 2%) [18].

In contrast to the contribution of AngII to atherosclerosis, infusion of Ang(1–7) reduces atherosclerosis in hypercholesterolemic mice without influencing blood pressure [19, 20]. There is a single study reported that AngIV infusion has no effect on the progression of atherosclerosis in mice, but leads to improved endothelial function of atherosclerotic lesions [21].

Angiotensin Peptide Receptors

Two receptor types have been the focus of many mechanistic studies on AngII effects. Of the two AngII receptor subtypes (AT1 and AT2), AT1 receptor is the predominant receptor for AngII biological and pathophysiological actions. In rodents, there are two subtypes of the AT1 receptor: AT1a and AT1b. Pharmacological inhibition that targets both AT1a and AT1b receptors results in profound reductions of experimental atherosclerosis in multiple animal models. There is a single report that AT1b receptor has no effect on AngII-induced atherosclerosis [22], while there are consistent findings that AT1a receptor deficiency reduces atherosclerosis in hypercholesterolemic mice [5, 23–25]. This AT1a receptor-specific role has also been demonstrated by that coadministration of an AT1 receptor antagonist, telmisartan, in Apoe^–/– mice with AT1a receptor deficiency does not further reduce atherosclerotic lesion size [25].

Reports on the role of AT2 receptor have been highly inconsistent, and include demonstrations that AT2 receptor deficiency attenuates [26], has no effects [5], augments [27], or changes cellularity without changing plaque size [28]. One study has shown that AT2 receptor overexpression through adenoassociated viral system decreases atherosclerosis in mice [29]. Comparably, pharmacological inhibition of AT2 receptor using PD123319 compound has also generated conflicting results as discussed earlier in Lu et al. [16]. It remains undefined what has caused these discrepant results regarding the contribution of AT2 receptor to atherosclerosis. Our previous study demonstrated that AT2 antagonism with PD123319 augmented atherosclerosis in hypercholesterolemic mice infused with AngII 1 μg/kg/min [30], inferring that AngII–AT2 receptor interaction may somewhat antagonize AngII–AT1 receptor interaction. A recent study reported that blockade of AT2 with PD123319 or inhibition of ACE with ramipril augmented atherosclerosis in hypercholesterolemic mice with AT1a receptor deficiency [25]. By contrast, infusion of AngII 0.4 μg/kg/min resulted in attenuation of atherosclerosis in AT1a receptor-deficient mice administered ramipril [25]. The findings from this article also imply that AngII–AT2 receptor interaction antagonizes atherosclerotic formation under certain conditions. However, it is unclear what receptors AngII interacts to augment atherosclerosis in both depletion of A...

Table of contents

• Cover
• Title page
• Table of Contents
• Contributors
• Foreword
• Preface
• Section I: Risk Factors: Old and New
• Section II: Cellular Mechanisms
• Section III: Molecular Mechanisms
• Section IV: Biochemical Mechanisms
• Section V: Clinical Management
• Index
• End User License Agreement