Reninangiotensin system and atherosclerosis
Karsten Grote,
Helmut Drexler and
Bernhard Schieffer
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany
Correspondence and offprint requests to: Bernhard Schieffer, MD, Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Email: Schieffer.Bernhard{at}MH-Hannover.de
Keywords: angiotensin II; AT1 receptor; atherosclerosis; inflammation; reninangiotensin system
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Introduction
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Cardiovascular (CV) events remain the main cause of morbidity and mortality in industrialized societies. Atherosclerosis is a chronic inflammatory disease [1] initiated and perpetuated by a variety of CV risk factors such as smoking, diabetes mellitus, hypertension and elevated plasma low-density lipoprotein (LDL) [2]. Atherosclerotic plaques are conglomerates composed of dysfunctional endothelial cells, smooth muscle cells, lipid-laden macrophages and T lymphocytes. These lipid-laden activated macrophages and T-lymphocytes stimulate their neighbouring cells to erode the collagen and elastin framework which forms the plaque's cap [15]. Myocardial infarction, stroke or sudden cardiac death are the fatal end-points of progressive atherosclerosis and are thought to be the result of these pathological remodelling processes [2]. Recent studies have identified morphological characteristics likely to be associated with a plaque's tendency to rupture, underlining the possibility of using such hallmarks clinically to predict, control and monitor plaque evolution. From a mechanical point of view, the delicate balance of plaque stability is controlled, on the one hand, by the intrinsic properties of the tissue and, on the other hand, by the external forces to which the plaque is subjected, i.e. mechanical forces of the blood flow and local formation of vasoconstrictors, such as angiotensin II (ANGII). Based on these observations, an increase in lipid content and a decrease in collagen content have been long suspected to reduce the mechanical strength of the plaque. Rapid recruitment of inflammatory cells together with local tissue release of chemoattractant factors therefore is not only one of the hallmarks of the atherosclerotic lesion but also at the origin of lesion formation. This process requires the concerted action of chemoattractants, cytokines and adhesion molecules. In this regard, the role of a hierarchical immuno-inflammatory response initiated by mechanical stress and/or LDL-cholesterol stimulates a cascade of mechanisms involving receptors of the innate immunity, i.e. Toll-like-receptors as well as cytokines, chemokines and eicosanoids. Central to many of these pathophysiological processes is the reninangiotensin system (RAS), specificically its effector peptide ANGII. Binding of ANGII to the angiotensin II type 1 (AT1) receptor induces calcium-dependent vasoconstriction, leading to an increase in systemic and regional blood pressure [3]. The direct relationship between blood pressure and the incidence of CV events is well accepted. The increase in risk can be attributed to structual and functional changes in target organs. In addition, AT1 receptor activation contributes independently to chronic CV disease by promoting vascular growth and proliferation, and endothelial dysfunction [4].
Here we focus on the impact of an activated RAS on atherogenetic plaque development and the therapeutic effects on atherosclerosis obtained by RAS inhibition.
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Activation of the reninangiotensin system in atherosclerosis
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Activation of the RAS may exert numerous adverse effects on the CV system (i.e. arterial hypertension, chronic renal failure and, potentially, atherosclerosis). Traditionally, the RAS has been described as an endocrine system in which renin of renal origin acts on angiotensinogen (an acute phase protein) of hepatic origin to produce angiotensin I in the plasma, which in turn is converted by pulmonary endothelial angiotensin-converting enzyme (ACE) to ANGII [5]. The latter is considered to be the main mediator of the physiological action of the RAS. Alternatively, ANGII can be produced directly by conversion of angiotensinogen by the tissue plasminogen activator (tPA), cathepsin G and tonin or by hydrolysis of angiotensin I by chymase and cathepsin G [6]. More recently, the importance of local tissue RAS [7], other angiotensin peptides (i.e. angiotensin III and IV) [8] and of the interaction with other systems, such as the endogenous kallikreinkininogenkinin system [9], was established. Regardless of the synthesis pathway, ANGII mediates its physiological effects by binding to specific receptors located on the cell membrane of various cell types, that are all vascular cells. It has also been recognized that although the majority of ANGII actions are exerted through AT1 [10] receptors, a seven-transmembrane domain G-protein-coupled receptor, which is strongly expressed on vascular smooth muscle cells (VSMCs), other specific cell surface receptors, including AT2 and AT4 receptors, and angiotensin (17) are also involved in the actions of angiotensin peptides [8,10].
The effects of ANGII include the following: (i) vasoconstriction; (ii) VSMC migration, proliferation and hypertrophy; (iii) increased extracellular matrix (ECM) formation; (iv) release of thromboxane A2; and (v) enhanced matrix metalloproteinase (MMP) production. More recent findings show (i) effects on plasminogen activator inhibitor-1 (PAI-1) synthesis [11]; (ii) activation of NAD(P)H oxidases [12]; and (iii) release of proinflammatory mediators, such as interleukin-6 (IL-6) [13]. Clinical consequences of these effects include an increase in blood pressure, myocardial and vascular hypertrophy and remodelling, and, potentially, plaque growth and rupture.
ANGII activates intracellular signalling pathways that promote atherosclerosis through the formation of reactive oxygen species (ROS), inflammation, growth, oxidation of LDL, endothelial dysfunction, matrix degradation and thrombosis.
ROS formation seem to be pivotal for the cross-link to inflammatory processes which contribute to atherosclerotic plaque formation. ANGII stimulation leads to an AT1/NAD(P)H oxidase-dependent formation of ROS [12,14]. These oxygen radicals are known activators of cytoplasmic signalling cascades, such as nuclear factor (NF)-
B, mitogen-activated protein (MAP) kinases and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [15]. Together, these mechanisms may enhance oxidative stress within the vessel wall and lead to the activation of redox-sensitive genes, such as those coding for proinflammatory cytokines like IL-6 [13].
Furthermore, NF-
B activation by ANGII leads to increased expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1 and E-selectin, and chemoattractant proteins such as monocyte chemoattractant protein (MCP)-1 [16] involved in adhesion and tissue recruitment of inflammatory cells. In addition, ANGII leads to the production of autocrine growth factors such as transforming growth factor (TGF)-ß1 and platelet-derived growth factor (PDGF), stimulating cellular hypertrophy and proliferation of smooth muscle cells [17].
Moreover, ANGII has important modulatory effects on vascular lipid metabolism in the vessel wall by enhancing LDL oxidation, involving the stimulation of lipoxygenase and NAD(P)H oxidase in macrophages [18]. An additional effect of ANGII is the upregulation of the lectin-like oxidized LDL receptor (LOX)-1 on endothelial cells and macrophages, an effect that may further enhance oxidized LDL infiltration in the vessel wall [19].
One of the earliest stages of atherosclerosis is functional abnormalities of the endothelium, named endothelial dysfunction. Enhanced shear stress produced by increased vascular load in concert with elevated levels of ANGII causes vessel wall remodelling, leading to the initiation, maintenance and destabilization of atherosclerotic lesions. Several different pathways appear to be involved: (i) upregulation of cytokines, growth factors and adhesion molecules; (ii) disturbances of lipid metabolism; and (iii) increased ROS production. In addition, inhibition of cellular growth, adhesion of proinflammatory cells and endothelial thrombogenicity occur in part through an impairment of endothelial nitric oxide (NO) secretion by ANGII, increasing oxidative stress by NAD(P)H oxidase stimulation [14]. Thereby, endothelial dysfunction and inflammation induced by ANGII trigger each other in a self-perpetuating feedback loop.
The development of atherosclerosis occurs through structural changes of the vessel wall from early migration and proliferation of smooth muscle cells up to plaque rupture. Enzymes which are involved in the degradation and reorganization of the ECM scaffold of the vessel wall called matrix metalloproteinases (MMPs) exhibit a marked local overexpression in the vulnerable shoulder region of human atheroma [20]. Recent unpublished findings from our laboratory show ANGII-enhanced expression and activity of MMP-2 in smooth muscle cells, which may promote plaque progession towards rupture. Finally, ANGII inhibits the fibrinolytic system and enhances thrombosis by increased production of plasminogen activator inhibitor (PAI)-1, tissue factor (TF), and platelet activation and aggregation [21].
Taken together, various largely overlapping ANGII-activated intracellular signalling pathways promote atherogenesis at every stage of its pathophysiological process.
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Why block the reninangiotensin system in atherosclerosis?
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ACE inhibitors in atherosclerosis
ACE inhibitors act by inhibiting the conversion of angiotensin I to ANGII. In addition, ACE inhibitors decrease the breakdown of bradykinin. Furthermore, ACE inhibitors, which increase tissue and plasma levels of angiotensin (17), may also improve the fibrinolytic balance by decreasing PAI-1 formation via angiotensin IV and/or reduced ANGII activation of AT4 receptors [22]. Since tissue ACE is highly expressed in human atherosclerotic plaques [23], where it is localized in areas of clustered macrophages, and is significantly increased in patients with unstable angina [24], it has been suggested that blocking ACE will prevent plaque fissuring, thrombosis and rupture.
A direct antiatherogenic effect of ACE inhibitors has also been shown in a variety of animal models. However, the largest body of evidence arises from landmark clinical trials such as the Heart Outcomes Prevention Evaluation (HOPE) study and the EUropean trial of Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) including patients with documented coronary artery disease (CAD) and preserved left ventricular (LV) function. Both trials demonstrated convincingly that CV events could be reduced in patients who were treated with an ACE inhibitor [25,26]. These large morbidity and mortality trials clearly support the role of ACE inhibitors in the treatment of atherosclerotic vascular diseases.
AT1 antagonists in atherosclerosis
The AT1 antagonists available for clinical use bind to the AT1 receptor with high affinity. AT1 antagonists reduce the activation of AT1 receptor-mediated actions of ANGII more effectively than ACE inhibitors since the latter do not reduce alternative, non-ACE ANGII-generating pathways, such as those involving chymase, cathepsin G or tonin. In contrast to ACE inhibitors, AT1 antagonists indirectly activate AT2 receptors. The importance of AT2-mediated effects is not clearly established. Nevertheless, recent evidence suggests that AT2 receptors may exert antiproliferative, proapoptotic and vasodilatory actions and may have a modest effect on promoting bradykinin release. ACE inhibitors increase angiotensin (17) levels more than AT1 antagonists, and this may result in additional beneficial cardiac and vascular effects. Moreover, ACE inhibitors increase the levels of a number of other ACE substrates that are not angiotensin peptides, including bradykinin. The increase in bradykinin levels may also contribute to the beneficial CV effects of ACE inhibitors. Whether or not these distinct pharmacological differences between AT1 antagonists and ACE inhibitors result in significant differences in therapeutic outcomes is not known at present.
Lastly, experimental studies have demonstrated that AT1 antagonists, especially losartan, may develop additional anti-aggregatory and anti-inflammatory actions. This latter may be of potential interest especially with regard to the treatment of patients with atherosclerotic diseases.
Experimental evidence in mice, rabbits and primates demonstrated convincingly that AT1 antagonists decrease cardiac and arterial medial hypertrophy and reduce the development of atherosclerotic lesions.
In clinical trials, it was shown that AT1 antagonists can effectively lower blood pressure and may positively influence atherosclerosis in hypertensive patients. However, unfortunately, there are no randomized, clinical trials to date on the effects of AT1 antagonists on the anatomic progression of atherosclerotic vascular diseases.
The Losartan Intervention for Endpoint reduction (LIFE) in hypertension study showed in 9193 patients, aged 5580 years with moderate to severe hypertension, a 13% (P = 0.021) lower primary event rate in the losartan-based treatment group. Interestingly, most benefit was related to a 25% reduction in the rate of strokes [27].
A renoprotective effect of AT1 antagonists was convincingly demonstrated in the Irbesartan Diabetic Nephropathy Trial (IDNT) [28], the Reduction of Endpoints in NIDDM (NonInsulin-Dependent Diabetes Mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) study [28] and the IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients trial (IRMA 2) [29]. CV end-points were pre-specified secondary outcomes in the RENAAL and IDNT studies. In the RENAAL study, the rates of fatal and non-fatal CV events did not differ significantly between the study groups, with the exception of hospitalization for heart failure, for which the risk was reduced by 32% in the losartan group. In the IDNT study, there was no significant difference in CV outcome between study groups. However, these studies, which enrolled <800 patients per study arm, were statistically underpowered to show significant differences in CV outcome. It remains speculative whether larger trials may show more clear-cut CV benefits and whether the renoprotective benefits demonstrated may be at least in part mediated by vascular protective actions of AT1 antagonists.
To date, we do not have any results from large-scale randomized AT1 antagonist trials in chronic atherosclerotic vascular diseases. However, trials such as the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) will enroll
23 000 patients
55 years old with a history of CAD, stroke or peripheral arterial disease, but without heart failure or known reduction in LV ejection fraction, and will compare major CV events in those treated with AT1 antagonists, ACE inhibitors or combined therapy. The Telmisartan Randomized Assessment Study in ACE-Inhibitor Intolerant patients with Cardiovascular Disease (TRANSCEND) trial will compare telmisartan with placebo in 5000 similar patients, who cannot tolerate ACE inhibitors. The ONTARGET and TRANSCEND trials are designed to test the hypothesis that AT1 antagonists and/or combined AT1 antagonists/ACE inhibitor treatment reduces atherosclerotic events.
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Conclusion
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The activation of the RAS may exert numerous deleterious CV effects in patients with atherosclerosis, hypertension and renal failure. Both ACE inhibitors and selective AT1 antagonists not only lower blood pressure levels effectively but also improve vascular structure and function. They thereby contribute to the reduction of ischaemic events and death beyond blood pressure lowering. It appears that ACE inhibitors should, therefore, be an essential part of the treatment regimen of patients with high-risk vascular disease, including normotensive individuals and those without heart failure and/or LV dysfunction. Based on experimental observations, it has been suggested that treatment with AT1 receptor antagonists may have similar beneficial effects on atherosclerotic vascular disease. However, to date, randomized clinical trials are still missing. Such randomized trials are currently ongoing and are expected to provide clear answers regarding the role of AT1 antagonists and/or combined AT1 antagonist/ACE inhibitor therapy in patients with CV disease.
Conflict of interest statement. None declared.
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