REVIEW Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade P Dandona, S Dhindsa, H Ghanim and A Chaudhuri Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, NY, USA Angiotensin II (Ang II) increases adhesion molecules, cytokines and chemokines and exerts a proinflamma- tory effect on leucocytes, endothelial cells and vascular smooth muscle cells. Acting via the type 1 receptor, Ang II initiates an inflammatory cascade of reduced nicoti- namide-adenine dinucleotide phosphate oxidase, reac- tive oxygen species (ROS) and nuclear factor-jB, which mediates transcription and gene expression and increases adhesion molecules and chemokines. An excess of ROS decreases nitric oxide bioavailability, causes endothelial dysfunction, and promotes athero- sclerosis. Moreover, Ang II interrupts the anti-inflamma- tory effects of insulin. Together, these effects promote a prothrombotic state as well as plaque rupture. Ang II receptor blockers suppress mediators of inflammation, including ROS and C-reactive protein, and they increase expression of inhibitory jB (an inhibitor of nuclear factor-jB). These anti-inflammatory and antioxidative effects, which are probably due in part to unopposed stimulation of the Ang II type 2 receptor, may be beneficial in acute coronary syndromes and may also contribute to the prevention of type II diabetes mellitus, as insulin resistance is mediated by inflammatory processes. Journal of Human Hypertension (2007) 21, 20–27. doi:10.1038/sj.jhh.1002101; published online 9 November 2006 Keywords: angiotensin II; angiotensin II receptor blockers; inflammation; oxidative stress; nuclear factor-kB; reactive oxygen species Introduction Angiotensin II (Ang II) is a powerful vasoconstrictor that induces the secretion of aldosterone and thereby the retention of sodium and water, which increases the circulating fluid volume and main- tains normal blood pressure in hypotensive situa- tions. In addition to its role in regulating blood pressure, Ang II has been shown to have important inflammatory and oxidative actions that are asso- ciated with atherosclerosis and acute coronary syndromes (Figure 1). Ang II is generated in the circulation (plasma) and in tissue – particularly the arterial wall. Endothelial cells are the major source of angiotensin-converting enzyme (ACE), which converts angiotensin I into Ang II. As Ang II is rapidly destroyed by angio- tensinases (half-life of approximately 1 min), local renin–angiotensin systems probably play an impor- tant role in vascular-wall pathophysiology. The two major classes of Ang II receptors are the type 1 (AT 1 ) and type 2 (AT 2 ) receptors. AT 2 receptors are not abundant in healthy adults; however, this class is upregulated in stressful conditions including vascular injury, myocardial infarction and heart failure. 1 The actions of Ang II mediated through AT 1 receptors – such as vasocon- striction and inflammation – oppose those mediated through AT 2 receptors, which include the release of nitric oxide (NO), an anti-inflammatory vasodilator that also reduces platelet aggregation and may facilitate the action of insulin. 2–9 When AT 1 recep- tors are inactive or blocked, the actions mediated by AT 2 receptors are likely to dominate. 3 Thus, block- ade of the renin–angiotensin system by angiotensin II receptor blockers (ARBs) may have dual effects: a decrease in vasoconstriction and aldosterone secre- tion accompanied by vasodilation mediated by an increase in NO. Relation of Ang II to oxidative stress and inflammation Ang II, acting via the AT 1 receptor, is likely to act as an inflammatory mediator through several mechan- Received 10 June 2006; revised 31 August 2006; accepted 1 September 2006; published online 9 November 2006 Correspondence: Dr P Dandona, Millard Fillmore Gates Circle Hospital, 10th Floor, 3 Gates Circle, Buffalo, NY 14209, USA. E-mail: pdandona@kaleidahealth.org Journal of Human Hypertension (2007) 21, 20–27 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh