Angiotensin II: one driving force behind atherogenesis.

Investigating the mechanisms of atherosclerosis, the number one cause of death in the civilized world, is an arduous task. During the last 5 decades, many aspects of atherosclerotic lesion development have been revealed and many hypotheses have been tested. Thanks to this gigantic effort, our knowledge of vascular biology and engaged pathogenic mechanisms have grown enormously. In spite of all this work, time, and money spent in thousands of laboratories all over the world, atherosclerosis remains something of an unsolved mystery. Every problem solved and every question answered raises even more questions and debates. This is largely because of the fact that there is not one single factor driving atherogenesis but many. However, there are some factors which have remained on stage for many years and from which a considerable part of the scientific community is willing to claim that these players deserve long-term attention. Among these, angiotensin II has been recognized as a major driving force behind endothelial dysfunction and atherosclerotic plaque development. Supposedly, generation of reactive oxygen species,1 activation of proapoptotic pathways, vascular smooth muscle cell (VSMC) proliferation,2,3 proinflammation,4 enhanced endothelial degeneration,5 and reduced vascular regeneration6 resemble mechanisms underlying the proatherosclerotic properties of angiotensin II. In the present issue of Hypertension, Weiss and Taylor investigated a low renin model of hypertension and present data which underline the key role of angiotensin II in atherogenesis.7 deoxycorticosterone acetate (DOCA) salt induced hypertension is an often used model. What makes this model unique is the fact that DOCA salt induced hypertension is accompanied with a decline in serum renin levels and a reduction in systemic angiotensin II release. One would imagine that this model might be well suited to investigate proatherosclerotic factors independent on Ang II. As shown by the Taylor group, ApoE / mice made hypertensive by implantation of DOCA salt tablets develop rapid atherosclerosis. Surprisingly, this effect is prevented by administration of either an angiotensin type 1 (AT1) receptor blocker or an angiotensin-converting enzyme (ACE) inhibitor. Of note, neither drug affected blood pressure, as assessed by the tail cuff method, in this DOCA salt model of hypertension and concomitant atherosclerosis. Weiss et al postulate that the described effects are not mediated via attenuation of the already weak systemic but the tissue connected renin-angiotensin-system (RAS) of the vasculature. This notion is supported by immunostainings showing elevated levels of angiotensin II, ACE, and the AT1 receptor in aortas of hypertensive ApoE / mice. Recent publications underline the finding that angiotensin II and the activated AT1 receptor are key players during the development of vascular lesions. It has been shown previously that angiotensin II infusion independently results in accelerated atherosclerosis and aneurysm formation on blood pressure in the same animal model.8,9 Doran et al investigated apolipoprotein (Apo)E / mice receiving high cholesterol diet and treatment with either an AT1 receptor antagonist or a calcium channel blocker. Only the AT1 receptor antagonist treatment attenuated the development of atherosclerotic lesions, although both drugs reduced blood pressure levels at the same rate.8 Furthermore, experiments in double knockout animals devoid of AT1 receptors and either ApoE or LDL receptors revealed that the absence of AT1 receptors profoundly reduced atherogenesis despite the fact that the lipid disorder prevailed.5 Two critiques which apply to all of these studies have to be mentioned. First, there is the fact that blood pressure measurements were taken via the tail cuff method which is less than ideal. Second, there are some limitations inherited in the DOCA salt model, eg, potential interactions between mineralocorticoid receptors and Ang II signaling as shown previously by several investigators.10 As already mentioned, underlying mechanisms of vascular lesion development involve oxidative stress, proinflammation, increased endothelial apoptosis, and impaired function of supposedly bone marrow–derived progenitors. However, the present article is not a mere confirmation of the already known facts, but importantly extends our understanding of the interplay of the RAS and vascular tissue. The animals used are not a model in which one would consider the RAS as a major problem at all—as is true for many of our patients who are not suffering from heart failure or acute large myocardial infarction and still are afflicted by atherosclerosis. Those observations suggest that the tissue-based components may be of even greater importance than the circulating hormones. One may speculate that (1) RAS inhibition adds antiatherogenic effects to the vasoprotective mechanisms mediated by blood pressure lowering alone and that (2) the tissue resident RAS might be of much higher importance than presently anticipated. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Medizinische Klinik und Poliklinik II, Innere Medizin, Universitätsklinikum Bonn, Germany. Correspondence to Cornelius Mueller, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany. E-mail [email protected] (Hypertension. 2008;51:175-176.) © 2008 American Heart Association, Inc.