Published online before print August 9, 2004, doi: 10.1161/01.HYP.0000140269.55873.7b
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(Hypertension. 2004;44:277.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Endogenous Angiotensin II Induces Atherosclerotic Plaque Vulnerability and Elicits a Th1 Response in ApoE–/– Mice
From the Service of Angiology (L.M., M.K., K.B., J.F.A., H.R.B., J.N., D.H.) and the Service of Hematology (M.A.D, V.V.), CHUV, University of Lausanne, Switzerland; Department of Pathology (H.H., G.G.), University of Geneva, Switzerland. H.H. is currently affiliated with the Department of Pathology, National Cardiovascular Center, Osaka, Fujishirodai, Japan.
Correspondence to Lucia Mazzolai, Service of Angiology, CHUV, University of Lausanne, 1011 Lausanne, Rue du Bugnon 46, Switzerland. E-mail lucia.mazzolai{at}chuv.hospvd.ch
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Abstract |
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Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE–/– mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE–/– mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE–/– mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE–/– mice had thinner fibrous cap (P<0.01), larger lipid core (P<0.01), and increased macrophage content (P<0.01) than even more hypertensive but normal angiotensin II ApoE–/– mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE–/– mice produced significantly higher amounts of interferon (IFN)-
than those from ApoE–/– mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN- production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.
Key Words: angiotensin • atherosclerosis • lymphocytes • interferon
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Introduction |
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Atherosclerosis is a multifactorial inflammatory disease recognized to be a major health burden in modern society. A number of risk factors are strongly associated with the initiation and growth of atherosclerotic plaques. However, mechanisms causing a stable plaque to become vulnerable remain largely unknown. This is especially important because atherosclerosis proceeds clinically silently over time as long as lesions remain stable; conversion to a vulnerable phenotype renders plaques susceptible to rupture with dramatic consequences such as acute coronary syndrome and stroke.1 For these reasons, stabilizing unstable plaques is a major goal in cardiovascular medicine, and it is therefore of great importance to understand the mechanisms that induce plaque vulnerability. A plaque is defined vulnerable when fibrous cap is thinned/absent, smooth muscle cell (SMC) content is low, lipid core is large (>50% total plaque surface), and inflammatory cells (mainly macrophages) accumulate within the lesion.1
The renin-angiotensin system (RAS), and particularly angiotensin (Ang) II, plays a key role in blood pressure homeostasis and atherogenesis through its hypertensive effect. Interestingly, several of the proposed mechanisms for atherogenesis are similar to those associated with Ang II-mediated events. In fact, Ang II alters lipid metabolism, SMC proliferation, coagulation, and behaves as a growth factor.2–5 Additionally, animal experiments and human studies both indirectly and directly demonstrated that pharmacological blockade of the RAS has beneficial effects on atherosclerosis.6–9 However, although Ang II has been hypothesized to play a role in plaque initiation and growth,10,11 to date there is no evidence for a direct effect of Ang II in plaque vulnerability.
Here, we provide the first evidence for Ang II-mediated plaque vulnerability in an in vivo model with increased endogenous Ang II production. We show that Ang II, beyond its hemodynamic effect, modulates the atherosclerotic phenotype from stable to vulnerable. We have evidence that Ang II-mediated atherogenesis progression is, at least in part, mediated by T helper (Th) type 1-like lymphocytes.
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Methods |
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Models of Renovascular Hypertension
Two models of renovascular hypertension were generated in ApoE–/– mice: (1) the renin-dependent 2, kidney-1 clip (2K1C), and (2) the renin-independent 1, kidney-1 clip (1K1C).12 Four weeks after clipping, mean blood pressure (MBP) and heart rate (HR) were measured.12 A group of 2K1C ApoE–/– mice was treated with an AT1 receptor blocker (3 ng/kg per day, Olmesartan, Sankyo, Japan). Plasma renin concentration (PRC) and plasma renin activity (PRA) were determined as previously described.13 Serum IL6, white blood cell count, and lipid profile were also assessed (for more detail, see the online supplement available at http://www.hypertensionaha.org).
Quantification of Atherosclerosis and Plaque Morphology
Quantification of atherosclerosis was determined in thoraco-abdominal aorta where morphology and morphometry analysis of plaques were performed in 3-µm-thick aortic sinus and brachiocephalic artery sections. For more details, see the online supplement.
Immunostaining
Sections were stained with a biotinylated mouse monoclonal IgG2a 
-SM actin antibody14 or with a rat monoclonal Mac-2 antibody (Cedarlane, Hornby, Ontario, Canada). For more details, see the online supplement.
Th1/Th2 Balance
Splenocytes from sham, 2K1C, and 1K1C ApoE–/– mice, 1 week after clipping, were purified. Interferon (IFN)- and IL4 ELISPOT (Bender Medsystems, San Bruno, Calif) and supernatant IL4, IL10, IFN- enzyme-lined immunosorbent assay (Mabtech, Mariemont, Ohio) were performed according to manufacturer indications. Additionally, cultured lymphocytes from sham ApoE–/– mice were stimulated with Ang II, with and without pretreatment with an Ang II AT1 receptor blocker, and IFN- production was determined. For more details, see the online supplement.
Statistical Analysis
For detailed statistical analysis, please see the online supplement.
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Results |
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Generation of ApoE–/– Mice With Increased Endogenous Ang II
To assess whether Ang II induces plaque instability, we generated the 2K1C hypertension model in ApoE–/– mice. In this model, the RAS is continuously stimulated and, therefore, endogenous renin and Ang II production increase.12,15 As controls we used similarly hypertensive 1K1C ApoE–/– mice with unchanged renin and Ang II levels, and sham normotensive ApoE–/– mice with normal Ang II. As expected, both high Ang II 2K1C and normal Ang II 1K1C ApoE–/– mice developed systolo-diastolic hypertension with an overall increase in pulse pressure (Table). As anticipated, PRC and PRA were significantly increased in high Ang II 2K1C (Table). PRC and PRA were not different between normotensive sham and hypertensive 1K1C ApoE–/– mice. No difference in HR and body weight was observed among the various groups of mice (Table). Lipid profile (total cholesterol, high-density lipoprotein, and low-density lipoprotein) was similar in all ApoE–/– mice (data not shown). Plasma creatinine levels were measured in all animals to ensure proper renal functioning. Results showed no significant difference among mice (data not shown).
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Ang II Induces a Switch From Stable to Vulnerable Plaques
Atherosclerosis developed in all animals. Location of plaques within the arterial tree was similar to that found in humans in areas where the hemodynamic environment predisposes to atherosclerotic development16 (online Figure IA to IF). In high Ang II ApoE–/– mice plaques were constantly present within the brachiocephalic trunk, whereas this vessel was relatively spared in normal Ang II ApoE–/– animals (online Figure IA, IC, IE). Interestingly, coronary artery atherosclerosis was found only in the high Ang II ApoE–/– mice (online Figure IG), probably because of accelerated atherosclerotic process rather than specific Ang II effect. Atherosclerosis quantification showed significant increase in lesion extension in hypertensive mice as compared with normotensives (online Figure IH). Surprisingly, high Ang II levels did not increase further atherosclerosis extension. However, staging and morphology of plaques significantly differed among the three groups of mice; 94% of high Ang II ApoE–/– mice developed advanced lesions (P<0.01 versus 1K1C and sham, n=14 to 16) (Figure 1 A and 1B). In contrast, only 7% of hypertensive normal Ang II animals had advanced plaques, 27% had early lesions, and 67% had intermediate ones (P<0.05 versus sham, n=14 to 16) (Figure 1C). All normotensive sham ApoE–/– mice had exclusively early lesions (Figure 1D). Characteristics of plaque vulnerability were assessed as follows. Presence of fibrous cap ensures a certain degree of stability, whereas its loss is associated with plaque rupture.17 In high Ang II ApoE–/– mice fibrous cap was absent/thinned in 100% of analyzed lesions (P<0.01 versus 1K1C and sham, n=14 to 16), whereas a thicker and continuous fibrous cap was present in all normal Ang II 1K1C ApoE–/– mice (Figure 1E and 1F). Fibrous cap is mainly composed of SMC, and SM content was significantly reduced (P<0.01) in fibrous cap of high Ang II compared with those from normal Ang II ApoE–/– mice (Figure 2 A to 2D). Fibrous cap detected within a lesion suggests occurrence of previous silent ruptures. These buried caps were observed exclusively in high Ang II ApoE–/– mice (P<0.01 versus 1K1C and sham, n=14 to 16) (Figure 1A). Increased lipid core size is linked to plaque vulnerability in humans.17,18 In our mice, total surface of central lipid/necrotic core exceeded 50% of total plaque surface in lesions from 81% of high Ang II 2K1C as compared with 7% of normal Ang II 1K1C ApoE–/– animals (P<0.01 versus 1K1C and sham, n=14 to 16). Signs of media degeneration were a prevailing characteristic of high Ang II ApoE–/– mice. Plaques from these animals showed elastic lamina fragmentation (P<0.01 versus 1K1C and sham, n=14 to 16) (Figure 1A and 1B) and media atrophy, characterized by -SM actin absence, likely caused by lipid accumulation (P<0.01 versus 1K1C and sham, n=14 to 16) (Figure 2A and 2B). Media atrophy was associated with intense adventitia inflammation (Figure 1B and Figure 2A). Mixed multiple cells layers at different stages are suggested to be the consequence of previous clinically silent ruptures and after de novo plaque growth.19 This phenomenon was observed in 75% of high Ang II 2K1C ApoE–/– (P<0.05 versus 1K1C and P<0.01 versus sham, n=14 to 16) and 33% of normal Ang II 1K1C mice (P<0.05 versus sham, n=14 to 16) (Figure 1A, 1B, and 1E). Adventitia inflammation was a striking characteristic found in 73% of high Ang II mice (n=15) (Figures 1B and 2
A). In human studies adventitia inflammation prevails in ruptured coronary plaques.20 This inflammatory process was totally absent in normotensive mice and found only in 20% of normal Ang II hypertensive 1K1C animals (P<0.05 in 2K1C versus 1K1C and P<0.01 versus sham, n=15). Polymorphonuclear cells were the prevalent cell type within the inflammatory areas and Mac-2 immunostaining revealed macrophage accumulation (Figure 2E). Macrophage plaque content was significantly increased in atherosclerotic lesions from high Ang II ApoE–/– mice (Figure 2E to 2G). This inflammatory reaction was already present 1 week after clipping suggesting that inflammation precedes development of vulnerable plaques. A number of studies have shown that ruptured plaques contain more inflammatory cells than nonruptured plaques.21,22 Presence of red blood cells within the plaque, independently from blood vessels, was observed exclusively in 19% of high Ang II 2K1C mice (Figure 1E).
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P<0.01 versus sham; n=10 to 16). E and F, Macrophage staining (Mac-2); E, 2K1C ApoE–/– mouse (thick white arrow indicates macrophage staining within the adventitia). F, 1K1C ApoE–/– mouse. G, Mac-2 quantification (*P<0.01 versus 1K1C and sham; n=10 to 16).To substantiate the role of Ang II as the inducer of plaque instability, mice (n=4) were treated with an Ang II AT1 receptor blocker before renal artery clipping (2K1C). In these mice, atherosclerosis extension was prevented and plaque surface was similar to that observed in sham nontreated animals (0.5% of total surface). Moreover, plaque staging and morphology was also comparable to that of nontreated sham ApoE–/– mice in that only early lesions were observed.
Th1/Th2 Imbalance in Mice With High Ang II
A prominent feature of mice with vulnerable plaques and high Ang II was enhanced inflammation. To evaluate the inflammatory state of these mice, serum IL6 and total white blood cell count were determined. High Ang II ApoE–/– mice showed a significant increase in circulating IL6 and white blood cells compared with normal Ang II ApoE–/– mice indicating an ongoing inflammatory reaction (online Figure IIA and IIB). Because of these observations, Th1 (producing IFN-) and Th2 (producing IL4 and IL10) profiles were evaluated in mice with high Ang II. Splenocytes from high Ang II ApoE–/– mice produced significantly higher amounts of IFN- than those from 1K1C and sham ApoE–/– animals (51±6.5, 18±8, and 21.4±7.1 ng/mL, respectively; P<0.05 in 2K1C versus 1K1C and sham; n=5 to 6), whereas secretion of IL4 and IL10 was not different among mice (online Figure IIC, IID). The shift in cytokine production toward a Th1 profile, in high Ang II ApoE–/– mice, was associated with significant increase in the number of IFN--producing splenocytes (1371±101/105 cells in 2K1C, 611±124/105 in 1K1C, and 746±111/105 in sham; P<0.01 in 2K1C versus 1K1C and sham; n=5 to 6). The graph depicted in online Figure IIE indicates the number of IFN--producing and IL4-producing splenocytes in each individual mouse showing a net shift in 2K1C mice toward a Th1 profile. A Th1-like subset of lymphocytes was also quantified from freshly isolated spleens. Results similarly demonstrated skewing toward IFN- production by high Ang II ApoE–/– mouse lymphocytes (data not shown), suggesting that Th1-like lymphocytes from high Ang II mice are selectively activated in vivo to produce IFN-. In additional experiments, cultured splenocytes from sham ApoE–/– mice were stimulated with Ang II (0.01 to 1 µmol/L). After stimulation, IFN- secretion significantly increased (Ang II 0.01 µmol/L: 251±16 pg/mL; Ang II 0.1 µmol/L: 316±28 pg/mL; Ang II 1 µmol/L: 368±21 pg/mL; in nonstimulated lymphocytes IFN- was below the detection limit of 8 pg/mL; n=5). This Ang II dose-dependent effect on IFN- secretion was blocked by pretreatment with an Ang II receptor blocker (Ang II 0.01 µmol/L: 15±7 pg/mL; Ang II 0.1 µmol/L: 16±7 pg/mL; Ang II 1 µmol/L: 27±8 pg/mL; P<0.05; in nonstimulated lymphocytes in presence of the AT1 blocker IFN- was below the detection limit of 8 pg/mL; n=5).
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Discussion |
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Results presented herein shed some light on the comprehension of the mechanisms responsible for transforming stable plaques into vulnerable ones. We show for the first time to our knowledge that Ang II induces a switch toward a vulnerable plaque phenotype, independently from its hemodynamic effect, and this progression is likely mediated by activation of lymphocytes toward a proinflammatory Th1-like phenotype. In our mice, increased endogenous production of Ang II is achieved through stimulation of renal renin secretion as it occurs in humans, thus taking into account all the physiological regulatory mechanisms. In fact, although Ang II levels are mainly regulated by circulating renal renin, as Ang II disappears from plasma and tissues after binephrectomy,15 local Ang II concentrations differ in various organs because other determinants, such as renin uptake, influence tissue Ang II concentrations.15
Hypertensive high Ang II ApoE–/– mice exhibited lesions with characteristics of instability, whereas plaques from even more hypertensive ApoE–/– mice (1K1C) but with normal Ang II levels displayed a stable phenotype. Atherogenesis was dramatically accelerated in the high Ang II mice, vulnerable plaques were already visible at 16 to 18 weeks of age. It is also noteworthy that in Ang II-independent hypertensive mice atherosclerosis extension was significantly increased compared with normotensive ApoE–/– animals. These observations demonstrate the important role of hypertension in atherosclerosis development. One could speculate that hypertension per se plays a role in the extension of the disease but that additional risk factors, such as high circulating Ang II, are needed to induce plaque vulnerability. Interestingly, a characteristic feature of mice with high Ang II was enhanced inflammation with increased macrophage accumulation and a skewed Th1-like lymphocyte profile. Ang II may influence recruitment and activation of macrophages into the vessel wall, presumably by influencing expression of proinflammatory chemokines. Ang II has been shown to increases monocyte chemoattractant protein-1 expression in cultured vascular SMC as well as monocytes.23 Th1-like lymphocytes participate in the regulation of inflammation by activating macrophages and recruiting phagocytic cells at the sites of "injury." Several authors have advocated a role for Th1 immunity on atherogenesis and, overall, atherosclerosis can be regarded as an inflammatory and reparative response to chronic or intermittent injury of the arterial wall.24–27 In this global picture, Ang II may be thought of as an accelerator that speeds up atherosclerosis by enhancing activation of a functional subset of T cells. Initial activation of effector T cells by Ang II may occur either indirectly or directly through mechanisms that are not mutually exclusive. Ang II is known to increase low-density lipoprotein oxidation and presentation of oxidized low-density lipoprotein by antigen presenting cells, such as macrophages, may trigger Th1-like cell differentiation.2 In the present report, we show that Ang II can directly affect IFN- production by ApoE–/– mouse splenocytes via the AT1 receptor.
Modulation of Th1-mediated inflammation by Ang II may play a role in plaque vulnerability in various ways. Inflammatory cells induce matrix-degrading metalloproteinases, whereas IFN- inhibits SMC proliferation and collagen synthesis, mechanisms that potentially predispose to fibrous cap rupture.28 Moreover, Th1-like cells and IFN- enhance monocyte production of thrombogenic tissue factor, contributing to plaque thrombogenicity.29,30 In our model, aldosterone was not measured and one may argue that stimulation of the RAS may be accompanied by an increase in aldosterone levels. Aldosterone is a known inflammatory mediator and, therefore, this possible mechanism of inflammation in our mice cannot be completely excluded.
Perspectives
In a multifactorial disease such as atherosclerosis, several factors play a role, and it is important to understand how strongly they relate to the disease and to each other. The hypertensive mouse models described herein enable us to study atherogenesis within the context of hyperlipidemia, hypertension, and high or low Ang II levels comparable to those found in humans. Results provide evidence for a new mechanism of plaque vulnerability, demonstrating that Ang II behaves as a local modulator promoting the induction of vulnerable plaques associated with a Th1 switch. This makes results relevant for understanding the human disease and provides tools for the development of new strategies aiming to prevent or stabilize vulnerable plaques.
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Acknowledgments |
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Supported by grants from the Swiss National Science Foundation to L.M., M.A.D., and D.H., and by an unrestricted grant from Sankyo. We thank Dr Erik Haesler and Irene Keller for their help.
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Footnotes |
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L.M. and M.A.D. contributed equally to the work.
Received May 7, 2004; first decision May 20, 2004; accepted June 14, 2004.
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