The development of atherosclerotic lesions is a chronic disease that proceeds through complex biochemical and cellular changes [1
]. The proposed mechanistic basis for many of the events in the initiation and maturation phases of lesion formation has involved aberrant metabolism of cholesterol transport. Indeed, we now have several decades of evidence that dysfunctional cholesterol metabolism is a major determinant of lesion development. However, more recently, substantial data have accumulated using genetic and pharmacologic approaches demonstrating a profound role for the renin angiotensin system (RAS) in experimental atherosclerosis. Although the RAS is a primary mediator of blood pressure and fluid balance, neither of these effects is the primary basis for the RAS to promote atherosclerosis. The consistent experimental literature has been complimented by a relatively uniform literature demonstrating a role for the RAS in human atherosclerotic disease.
The classical RAS synthesis pathway consists of a simple two-step enzymatic process in which angiotensinogen has 10 amino acids cleaved from the N terminus by renin and a subsequent removal of two further amino acids by angiotensin-converting enzyme (ACE) to yield the bioactive octapeptide, angiotensin II (AngII). Although the principal source of angiotensinogen, renin, and ACE have been the liver, kidneys, and lungs, respectively, there are evolving complexities of the location of these components. There is also a growing appreciation that other bioactive angiotensin peptides can be generated by more recently recognized RAS enzymes such as aminopeptidases and a homologue of ACE, termed ACE2. Therefore, it has now been defined that the RAS generates a range of bioactive peptides, some of which have direct antagonistic effects to each other [2
The principal receptor mediating most of the described effects of AngII is the AT1 receptor, which is a seven transmembrane G protein–coupled receptor [3
]. AT1 receptors are expressed in most major organs. There is a highly consistent literature regarding the role of AT1 receptors mediating many of the physiologic and pathologic effects of AngII. AT1 receptors undergo a chromosomal duplication resulting in the expression of two closely related subtypes that have been termed “a” and “b” in rodents. These receptors have 96% sequence similarity and are indistinguishable by pharmacologic approaches. The majority of the sequence variations between the subtypes are in the C-terminal intracellular region. Although poorly defined, sequence differences in these intracellular regions have the potential to mediate subtype-specific responses to AngII through complex signaling pathways [4
••]. The predominance of AngII effects in rodents are via stimulation of AT1a receptors, although effects such as aortic contractions appear to be AT1b receptor-dependent [5
]. AngII also stimulates AT2 receptors that are frequently considered to antagonize the effects of AT1 receptor stimulation. AT2 receptors are highly expressed in fetal tissues, but the abundance of the receptor markedly declines after birth. Unlike AT1 receptors, the functional consequences of AngII stimulation of AT2 receptors have generated an inconsistent literature in which effects are generally modest.
In animal studies, the predominance of the studies to determine a link of the RAS to atherosclerosis has been performed using genetically engineered mice to change receptor expression. This has also been combined with bone marrow transplantation to elucidate the role of a specific AngII receptor on cells on atherosclerosis. The experimental studies have the advantage of being able to retrieve atherosclerotic tissues to enable a direct measurement of size and characteristics of lesions. Obviously, studies in humans are not able to directly interrogate atherosclerotic tissues. Although imaging modalities are improved, insightful approaches have not been applied to the genetics of the RAS in the human disease. Therefore, a caveat of comparing experimental to human studies is the latter predominantly use indirect end points of atherosclerosis-associated diseases such as acute myocardial infarction and stroke.