Renin-angiotensin system and coronary artery disease - Interaction of angiotensin II with pro-inflammatory cytokines in human stable and unstable coronary plaques

Elevated inflammatory markers, such as cytokines (e.g., interleukin 6) and acute phase reactants (C-reactive protein and serum amyloid A) are one of the characteristics of patients with acute coronary syndromes (ACS). In addition, patients with genetically determined elevated serum levels of components of the renin angiotensin system (RAS) have a higher risk of myocardial infarction (MI). Inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors reduces the risk of re-infarction in patients after MI as shown in large scale clinical trials, such as SAVE, SOLVD, and AIRE. Angiotensin III the effector peptide of the RAS activates via its G-protein coupled type 1 receptor (AT(1)) the cascade of Jak kinases and transcription factors of the STAT family (signal transducers and activators of transcription) which is traditionally involved in cytokine induction. In-vitro experiments demonstrated that an activated RAS, via the JAK/STAT cascade, interacts with proinflammatory cytokines, e.g., Il-6, which in turn induces the release of prothromobotic factors, such as plasminogen activator 1 and the synthesis of acute phase reactant C-RP and alpha 2-macroglobulin. Blockade of the either the AT(1) receptor or the tyrosine kinase JAK2 abolished this effect. Moreover, in-vivo findings obtained by immunhistochemistry in explanted human coronary arteries revealed that ACE, AII, AT, receptor, and IL-6 are co-localized with macrophages (CD68 positive cells) at the shoulder region of the plaque. Similarly, co-localization of ACEI AII, AT(1) receptor and Il-6 was documented in atherectomy samples obtained from patients with unstable angina and AII was localized in close proximity to the presumed rupture site of human coronary arteries in acute MI. Thus, these results emphasize that the renin angiotensin system may contribute to inflammatory processes within the vascular wall and thereby may amplify the development of an acute coronary syndrome.