ABSTRACT
The classically defined RAS contains a major bioactive peptide, AngII, derived from one substrate, angiotensinogen, and two critical enzymes, renin and ACE. The most abundant sources of these components of the RAS are liver for angiotensinogen, kidneys for renin, and lungs for ACE.22 AngII exerts its bioactive effects through binding to AngII receptors, AT1 and AT2 receptors, that are expressed by many cell types. Many of the AngII actions are via stimulation of AT1 receptors, a seven transmembrane type G-protein-coupled receptor that is encoded by one gene (AGTR1) in humans. Rodents have undergone a chromosomal duplication that leads to expression of two highly homologous isotypes of AT1 receptors, termed Agtr1a and Agtr1b. Numerous intracellular signaling pathways can be activated by AngII stimulation of AT1 receptors.23 AT2 receptors are transcribed from an X-linked gene.24 It is also a seven transmembrane type G-protein coupled receptor that has low (34%) homology to AT1 receptors.25 Several signaling pathways that are stimulated by
AngII interaction with AT2 receptors are inhibitory of AT1 receptor stimulation.26 This has contributed to the concept that AT2 receptor stimulation opposes the effects of AT1 receptor stimulation, although it has not been uniformly accepted.27 More recent studies have led to an expansion of the RAS that has additional bioactive peptides, cellular sources of proteins and enzymes, and other receptors. The complexity of this system includes several aspects. First, there is an identification of a full complement of the RAS components in many organs and specific cell types.28 In regard to atherosclerosis, cells endowed with the ability to synthesize the RAS components include macrophages,13 mast cells,29,30 adipocytes,31 and smooth muscle cells.32 Second, there is a recognition of a spectrum of bioactive angiotensin peptides and their corresponding receptors. This includes Ang(1-7) that is synthesized from AngII by ACE2 and exerts its effect via mas receptors.4,33,34 Also, AngIV, an aminopeptidase product from AngII, interacts with AT4 receptors.35 Third, some components of the RAS exert effects independent of angiotensin peptides. This includes the direct effect of renin on the renin receptor and the diverse nature of substrates for ACE and ACE2.36−38 Fourth, the complexity of the RAS is also exhibited by the discovery of alternative enzymes, other than renin and ACE, to generate AngII. This includes chymase, an enzyme produced mainly in mast cells that has been proposed as a major contributor to the conversion of AngI into AngII in atherosclerotic tissues.30 Overall, while the RAS is a potent regulator of atherosclerosis, its complexity has hindered the determination of the mechanisms of this regulation. 8.3 Regulation of Experimental
Atherosclerosis by the RASThere is considerable evidence that the RAS promotes and augments atherosclerosis. This originates from studies in animal models using pharmacological and genetic approaches that predominantly target the bioactive molecule, AngII. Earlier theories regarding this complex system placed emphasis mostly on indirect effects of AngII, in particular its promotion of lesion formation through increasing blood pressure. However, the more contemporary thought is that AngII has a direct effect on the arterial wall to promote atherosclerosis.39
