Interactions Between the Renin–Angiotensin System and  Dyslipidemia: Relevance in Atherogenesis and  Therapy of Coronary Heart Disease

BK Singh, JL Mehta
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Arkansas for  Medical Sciences and the  Central Arkansas Veterans Healthcare System,  Little Rock, AR, USA

Hypercholesterolemia and hypertension are major risk  factors for coronary heart disease, and both are often  present in the same patient. It is thought that interactions  between dyslipidemia and activation of neurohumoral  systems such as the renin–angiotensin system (RAS) may  not only explain the frequent coexistence of hypertension  and dyslipidemia, but may also play an important role in  the pathogenesis of atherosclerosis. Experimental data  suggest that there is a correlation between the effects of  angiotensin II (Ang II) and lipoproteins on atherogenic risk.  Data from recent experimental and clinical studies suggest  that the pathways by which Ang II and low-density  lipoprotein (LDL)-cholesterol lead to vascular disease may  frequently overlap. Interventions directed at lowering total  cholesterol, LDL-cholesterol and triglyceride levels, and  raising high-density lipoprotein (HDL)-cholesterol levels  result in a reduction in cardiovascular events. Control of  blood pressure results in a similar decrease in cardiovascular  events. Angiotensin-converting enzyme (ACE) inhibitors or  angiotensin type 1 (AT 1 ) receptor blockers modulate RAS  and are beneficial in reducing cardiovascular events in  patients with vascular disease. There is a suggestion that  the combined use of cholesterol-lowering drugs along with  agents that modulate RAS may have additive benefit.  

In this review, we discuss the results of experimental and  clinical studies on the interaction between RAS and  dyslipidemia. These observations may have an impact on  the therapy of patients with coronary heart disease. 

Renin–Angiotensin System and Cholesterol  Biosynthesis 

Cholesterol accumulation in the macrophages and their  transformation into foam cells are major events in the  development of atherosclerosis. Cellular cholesterol  accumulation can result from increased uptake of LDL or  oxidatively modified forms of LDL,1 as well as by enhanced  macrophage cholesterol synthesis. Using macrophages  harvested from the peritoneum after injection of Ang II,  Keidar et al.2 were able to demonstrate that Ang II  dramatically increased macrophage cellular cholesterol  biosynthesis with no significant effect on blood pressure or  on plasma cholesterol levels. The ACE inhibitor fosinopril  and the AT1 receptor blocker losartan decreased cholesterol  biosynthesis in response to Ang II. Further, in cells that lack  the AT1 receptor (RAW macrophages), Ang II did not  increase cellular cholesterol synthesis. These observations  confirm the role of the AT1 receptor in Ang II-mediated  cholesterol synthesis by macrophages. Other studies by  Nickenig et al.3 have shown accumulation of LDL-cholesterol  in cultured vascular smooth muscle cells and  this effect is mediated via AT1 receptor activation. 

Angiotensin II-mediated increase in macrophage  cholesterol influx has been demonstrated, and attributed  to the oxidant stress contributing to and facilitating LDL  oxidation by arterial wall components.4 Angiotensin II can  also bind to LDL and form modified lipoprotein, which is  taken up at an enhanced rate by the macrophages scavenger  receptor, leading to cellular cholesterol accumulation.5 Li  et al.6 studied the kinetics of oxidized LDL (ox-LDL) uptake  in endothelial cells and observed that Ang II, in a  concentration-dependent fashion, enhanced the uptake of  I 125 labeled ox-LDL in these cells. The AT1 receptor blocker  losartan, but not the AT2 receptor blocker PD 123319,  blocked the enhanced uptake of ox-LDL. 

Fluvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, blocks  the stimulatory effect of Ang II on macrophage cholesterol  biosynthesis.2 Further, Ang II has been shown to upregulate  macrophage mRNA for HMG-CoA reductase.2 The  biochemical site of action for Ang II along the cholesterol  biosynthesis pathway is probably HMG-CoA reductase, the  rate-limiting enzyme in cholesterol biosynthesis.7    

Thus it appears that stimulation of cholesterol  biosynthesis in macrophages, uptake of LDL in smooth  muscle cells and ox-LDL in macrophages and endothelial  cells requires, or is at least facilitated by, AT1 receptor  activation. In this process, alteration in the expression of  HMG-CoA reductase may play an important role.

Renin–Angiotensin System, Dyslipidemia and  Reactive Oxygen Species (ROS) 

Griendling et al.8 first documented that Ang II increases  nicotinamide adenine dinucleotide (phosphate) hydroxide  (NADH/NADPH) oxidase activity in macrophages via AT1  receptor activation. Increased oxidative stress is now  regarded as an important feature of hypercholesterolemic  atherosclerosis. In this context, antioxidants have been  shown to reduce the extent of progression of atherosclerosis  in experimental animals and, in some studies, in humans  as well.  

Warnholtz et al.9 studied superoxide production in the  aorta of rabbits fed on a diet containing 0.5% cholesterol.  In their first study, they looked at the effects of endothelium  removal on vascular superoxide production in control and  Watanabe rabbits (hypercholesterolemia secondary to an  LDL receptor defect). The rate of superoxide production was  increased approximately two-fold in aortic segments from  Watanabe rabbits compared with rabbits fed a normal diet  (controls). This increase in superoxide production was  abolished by removal of the endothelium from the arterial  segments. In these segments, NADH oxidase but not  NADPH activity was significantly increased. These findings  suggested that hypercholesterolemia is associated with  increased superoxide production secondary to activation of  vascular NADH oxidase. These authors then measured the  effects of an AT1 receptor blocker (Bay 10-6734) on  superoxide production and NADH oxidase activity in aortas  from the controls and rabbits fed a high-cholesterol diet.  The administration of an AT1 receptor blocker reduced  superoxide production and inhibited NADH oxidase activity  in cholesterol-fed animals. The investigators concluded that  in hypercholesterolemic animals, NADH oxidase represents  a major vascular source of superoxide and that increased  vascular levels of Ang II may cause increased NADH oxidase  activity. Hypercholesterolemia is associated with AT1  receptor upregulation, endothelial dysfunction and  increased NADH-dependent vascular superoxide  production. The improvement in endothelial dysfunction,  inhibition of the oxidase and reduction of early plaque  formation by an AT1 receptor antagonist suggests that Ang  II-mediated superoxide production plays a crucial role in  the early stage of atherosclerosis. Clinical and experimental  studies have identified a marked attenuation in  endothelium-dependent vasodilatation as one of the early  stages in atherosclerosis.10,11 In some cases, this is related  to enhanced inactivation of endothelium-derived nitric  oxide (NO) by superoxide,12 rather than a consequence of  decreased NO production.13 It is known that AT1 receptor  activation leads to membrane-associated NADH-dependent  oxidase.8 Low-density lipoprotein enhances AT1 receptor  expression in cultured smooth muscle cells14 and  atherosclerotic lesions are associated with increased ACE  expression,15 which may serve as a source for local  production of Ang II and, ultimately, increased stimulation  of vascular superoxide production.  

A number of studies have shown that AT1 receptor  blockade normalizes the activity of NADH oxidase, reduces  plaque area and macrophage infiltration, and  simultaneously improves the endothelial surface in animals  fed a high-cholesterol diet.16 These findings suggest that  RAS plays a pathogenic role in both the initiation and  acceleration of the atherosclerotic process and that  inhibition of RAS may benefit the treatment of this malady.

Long-term treatment with ACE inhibitors has been  shown to improve endothelial vasomotor function in  patients with coronary artery disease (Trial on Reversing  Endothelial Dysfunction, TREND),17 possibly because of  decreased superoxide-mediated inactivation of NO.  Importantly, the benefits of ACE inhibitor therapy are more  pronounced in patients with hypercholesterolemia. 

Hypercholesterolemia and RAS activation  

Experimental studies have shown that hyperlipidemia  enhances RAS activity. All components of increased RAS  activation have been identified in hyperlipidemic  atherosclerotic lesions. These include, in particular,  increased expression of ACE and AT1 receptors.18,19 A  number of recent studies of human atherosclerotic tissues  have confirmed the upregulation of ACE and AT 1 receptors,  particularly in the regions that are prone to plaque  rupture. 20 Importantly, these areas show extensive  inflammatory cell deposits, macrophage accumulation and  apoptosis.  

In vitro studies have shown that incubation of vascular  smooth muscle cells with LDL increases expression of AT1  receptors.21 Li et al.22 examined the expression of Ang II  receptors in human coronary artery endothelial cells, and  observed that ox-LDL increases the mRNA and protein for  AT1 , but not AT2 receptors, implying that ox-LDL increases  AT1 expression at the transcriptional level. In this process,  activation of the redox-sensitive transcription factor NF-kB  plays a critical role. To define the relationship of RAS and  lipids in humans, Nickenig et al.3 administered Ang II in  normocholesterolemic and hypercholesterolemic men, and  found that blood pressure was increased in the  hypercholesterolemic group and this response could be  blunted by LDL-cholesterol lowering agents. Further, these  investigators found that there was a linear relationship  between AT1 receptor density on platelets and LDL-cholesterol  concentration in plasma. Treatment with statins  decreased the AT1 receptor expression in this study. Statin-mediated  downregulation of AT1 receptor expression has  also been shown in vascular smooth muscle cells.23 A recent  study has shown that statins directly decrease AT1 receptor  expression in endothelial cells.24  

The expression of genes for chymases—enzymes by  which Ang II can be formed independent of ACE  activation—has been shown to increase in atherosclerotic  lesions of the aorta of monkeys fed a high-cholesterol diet.25  The functional significance of chymase in the development  of atherosclerosis, however, remains uncertain. 

Role of Ang II in Hypercholesterolemic  Atherosclerosis  

Activation of RAS with formation of Ang II and activation  of Ang II receptors, particularly AT1 receptors, has been  implicated in the pathobiology of atherosclerosis, plaque  rupture, myocardial ischemic dysfunction and congestive  heart failure.26 Several studies show that ACE inhibitors  decrease progression of atherosclerosis in a variety of  animal species.27,28 Since a number of different ACE  inhibitors exert similar anti-atherosclerotic effects, one can  assume that this represents a class effect. In concurrence  with slowing of the progression of atherosclerosis, ACE  inhibitors decrease markers of inflammation and LDL  oxidation in the atherosclerotic regions.  

A variety of AT1 receptor blockers have also been shown  to reduce the progression of atherosclerosis in different  animal models.28,29 The effects are particularly evident at  high doses of AT1 receptor blockers, which suggests  that either high doses block AT1 receptors more completely  than lower doses, or that high doses reduce atherosclerosis  by some nonspecific effect. We recently reported the anti-atherosclerotic  effect of losartan (25 mg/kg) in  rabbits fed a high-cholesterol diet and showed that losartan  therapy suppressed the expression of adhesion molecules  as well as by activating its regulatory protein 29

To determine the specificity of the role of RAS inhibitors  (v. the blood pressure-lowering effect), Leif et al.28 conducted  a study with low doses of fosinopril (5 mg/kg/day) or  losartan (5 mg/kg/day) that did not lower blood pressure.  Control animals were given either a placebo or a dose of  hydralazine which lowered blood pressure. Low-density  lipoprotein oxidation, as measured by levels of  thiobarbituric acid-reactive substances (TBARS) or by  formation of conjugated dienes, was suppressed by low-dose  fosinopril, suppressed only modestly by losartan and  unaffected by the placebo or hydralazine. Atherosclerosis  was inhibited by fosinopril and losartan, suggesting that the  anti-atherosclerotic effects of RAS inhibitors may be due,  at least in part, to direct inhibition of LDL oxidation and  other effects of Ang II on the vessel wall. 

Bavry et al.30 from our laboratory showed that the ACE  inhibitor quinapril decreased intra-arterial thrombus  formation, whereas the AT1 receptor blocker losartan had  a minimal effect. The inhibitory effect of ACE inhibitors on  the generation of plasminogen activator inhibitor-1 may  be relevant in this differential effect of ACE inhibitors and  AT1 receptor blockers. This is especially relevant since  thrombosis is intimately involved in atherogenesis.31  

The role of Ang II in promoting atherosclerotic lesions  and aneurysms in apolipoprotein (apo) E-deficient mice has  been recently examined by Daugherty et al.32 These  investigators showed that a 1-month infusion of Ang II  enhanced the severity of aortic atherosclerotic lesions  compared to a placebo. Interestingly, there was extensive  formation of abdominal aortic aneurysms in apo E-deficient  mice infused with Ang II. Further, the presence of  hyperlipidemia was necessary for the development of  aneurysms. These observations suggest that increased  plasma concentrations of Ang II have profound effects on  vascular pathology when combined with hyperlipidemia,  and inhibitors of RAS may have a therapeutic benefit,  especially in the hyperlipidemic state. 

Endothelial function, RAS and Dyslipidemia

Endothelial dysfunction in hypercholesterolemic animals  has been shown to be improved by ACE inhibitors.33  Bradykinin antagonists can diminish some of this benefit,  suggesting that inhibition of bradykinin breakdown rather  than inhibition of Ang II formation may be important in  this effect.34 Recently, Mancini et al.17 showed that treatment  of patients with coronary artery disease with quinapril  improved coronary vasomotion. Quinapril had greater  efficacy in improving endothelial function in patients with  LDL-cholesterol >130 mg/dl than in patients with LDL-cholesterol  <130 mg/dl.13–18 

Acetylcholine stimulates release of the potent  vasodilator species NO, which is broken down by ROS. One  of the mechanisms responsible for improvement in  acetylcholine-mediated vasodilatation may be inhibition of  Ang II-sensitive, NADH-dependent, superoxide-producing  enzymes, resulting in a reduction of NO inactivation.  Warnholtz et al.9 showed that AT1 receptor blockade  inhibited NADH oxidase activity and simultaneously  improved endothelial dysfunction in animals fed a high-  cholesterol diet. These findings cannot be attributed to  lowering of cholesterol levels because treatment with the  AT1 receptor blocker has no effect on total or LDL-  cholesterol level. 

Interaction between ox-LDL and RAS:  Role of Receptors for ox-LDL (LOX-1) 

We have recently identified high-affinity lectin-like  receptors for ox-LDL (LOX-1) in cultured human coronary  artery endothelial cells byreverse transcriptase-polymerase  chain reaction (RT-PCR), Western blot, and radioligand  binding.35,36 Native LDL does not bind to this receptor.  Vascular endothelial cells in culture37 and in vivo38 internalize and degrade ox-LDL through this putative  receptor-mediated pathway which does not seem to involve  the classic macrophage scavenger receptor. Recent studies  show that the cytokine TNF-a39 and fluid shear stress40  markedly upregulate LOX-1 gene expression. Activation of  LOX-1 is involved in apoptosis (programmed cell death) in  response to ox-LDL,41,42 mitogen-activated protein kinase  (MAPK)-1 activation,andexpressionof adhesionmolecules  and attachment of monocytes to activated endothelial  cells.43 A critical role is played by in the effect ox-  LDL has on endothelial cells. 23 The pro-apoptotic effect of  Ang II in human coronary artery endothelial cells and the  role of AT1 receptor and protein kinase C (PKC) activation  have also been shown by our group.44  

Li et al.36 from our laboratory have demonstrated that  Ang II upregulates LOX-1 expression as well as the uptake  of ox-LDL in human coronary artery endothelial cells via  activation of the AT 1 receptor. The effects of Ang II were  blocked by the AT1 receptor blockers losartan and  candesartan, but not by the AT2 receptor blocker PD  213319. Angiotensin II and ox-LDL exerted a cumulative  injurious effect on cells, measured as lactic dehydrogenase  (LDH) release and cell viability. Again, AT1 receptor blockers  reduced the cumulative injurious effect of Ang II and ox-  LDL. Importantly, the chain-breaking antioxidant a -  tocopherol also attenuated the injurious effect of ox-LDL  and Ang II, emphasizing the importance of redox-sensitive  pathways in the cross-talk.45  

The cross-talk between ox-LDL and Ang II is further  evident from the work of Chen et al.29 from our laboratory,  who showed intense immunostaining for and upregulation  of the gene for LOX-1 in the atherosclerotic tissue of rabbits  fed a high-cholesterol diet. Losartan therapy not only  reduced atherosclerosis, but also blocked the upregulation  of LOX-1. Recent unpublished studies from our laboratory  show marked upregulation of LOX-1 in concert with  apoptosis in human atherosclerotic plaques, particularly in  the regions that are prone to rupture. Figure 1 shows the  interaction of dyslipidemia and RAS in atherogenesis.

Dyslipidemia and RAS in Hypertension  

The association of hypertension with hyperlipidemia has  been noted in several population studies.The prevalence of  hypertensionisgreaterin populationswithhighcholesterol  levels.46 Dyslipidemia may be another metabolic factor that  influencesbloodpressure.However, thesestudiesusedolder,  less rigorous definitions than are currently recommended.  Recently, Lloyd-Jones et al.47 evaluated 4962 subjects from  the Framingham Heart Offspring Study and cross-clarified  them according to the sixth Report of the Joint National  Committee on the Prevention, Detection, Evaluation, and  Treatment of High Blood Pressure (JNC VI). Data were  collected from subjects examined between 1990 and 1995.  The prevalence of dyslipidemia (defined as total  cholesterol >240 mg/dl, HDL-cholesterol <35 mg/dl, or  currently receiving lipid-lowering therapy) increases  with increasing blood pressure in men and women. On  an average, over 40% of men and 33% of women with  blood pressure >145/>90 mmHg were also dyslipidemic.  These data demonstrate that hypertension and  hypercholesterolemia are frequently associated, even when  current rigorous definitions are used. These observations  also suggest that individuals with hypertension may be  more likely to become dyslipidemic over time.  

Sung et al.48 examined the blood pressure response to a  standard mental arithmetic test in 37 healthy normotensive  subjects with hypercholesterolemia (mean total cholesterol  263 mg/dl) and 33 normotensive subjects with normal  cholesterol levels. None of the hypercholesterolemic group  was receiving lipid-lowering therapy prior to induction in  the study. In the first part of the study, blood pressure  response during the arithmetic test was determined and  found to be significantly higher in the hypercholesterolemic  group compared with the normocholesterolemic group (18  v. 10 mmHg, respectively, p<0.005). In the second part of  the test, the hypercholesterolemic group was divided into 2  subgroups which received either 6 weeks of lovastatin or 6  weeks of placebo in a double-blind, cross-over design. There  were 26 evaluable patients in this part of the study. Statin  treatment resulted in significant reduction from baseline  in total and LDL-cholesterol levels and was associated with  lower mean systolic blood pressure prior to (119±11 v.  122±9 mmHg, p=0.07) and during the arithmetic test  (133±12 v. 141±10 mmHg, p<0.05). Diastolic blood  pressure changes were not significantly correlated with  lowering of lipid levels. These observations demonstrate that  individuals with hypercholesterolemia have an exaggerated  systolic blood pressure response to mental stress and the  lowering of lipid levels improves the systolic response to  stress. Although the effects of elevated cholesterol levels on  atherosclerosis are well documented, the modest change in  the degree of stenosis demonstrated by angiographic studies  is not sufficient to explain the benefit of reduction in  cholesterol levels. It may well be that lowering cholesterol  levels alters the activity of some neurohumoral mediators  such as Ang II and improves vascular tone. 

Nazzaro et al.49 made an interesting observation of the  combined and distinct vascular effects of ACE inhibitors  and statins on lowering blood pressure. They examined  the effects of lowering of lipid levels on blood pressure in a  study of 30 subjects with coexisting hypertension and  hypercholesterolemia. Subjects received a placebo for 4  weeks and were then divided into 2 groups. Each group of  15 patients received monotherapy with either simvastatin  10 mg or enalapril 20 mg for 14 weeks. After the  monotherapy phase, each group received both drugs for an  additional 14 weeks. Blood pressure was measured during  stressful stimuli such as the Strop color test and the cold  pressor forehead test. As expected, enalapril lowered blood  pressure. Interestingly, however, simvastatin also lowered  blood pressure (although to a lesser extent) and the  combination of both medications achieved greater blood  pressure reduction than either alone. These observations  suggest a close interplay of RAS and lipid metabolism. 

Nazzaro et al.49 also measured post-ischemic forearm  blood flow and minimal vascular resistance to evaluate the  effects of mental stress on vasodilatative capacity and  vascular structure, respectively. These parameters  demonstrated the same trends as blood pressure. Both  monotherapies improved these parameters, but the  combination therapy was associated with a greater  improvement than either monotherapy. These findings  suggest a cross-talk between dyslipidemia and RAS relative  to vascular dynamics. Table 1 shows the common effects  of dyslipidemia and RAS in atherosclerosis. 

Clinical Benefit of Modulation of RAS and  Dyslipidemia in Coronary Artery Disease (CAD)  Although numerous epidemiological studies have shown  that elevated levels of LDL are associated with the onset of  hypertension and atherosclerosis,50 the underlying  mechanisms remain unclear. Angiotensin-converting  enzyme inhibition has been shown to promote regression  and even prevent atherosclerosis, suggesting a link between  atherosclerosis and RAS.51 

The clinical benefits from simultaneous modulation of  RAS and dyslipidemia are summarized in Table 2. Indirect  evidence for an interaction between dyslipidemia and RAS  comes from some clinical studies such as Evaluation of  Losartan In the Elderly (ELITE)52 and Lipoprotein and  Coronary Atherosclerosis Study (LCAS).53 There are studies which suggest that RAS may affect responses to lipid-lowering  agents. Observations from unpublished data from  studies such as the ELITE trial support the hypothesis that  combination treatment with ACE inhibitors and statins may  have incremental benefit in reducing mortality.  

The LCAS was conducted in 429 patients with CAD and  at least 1 lesion with 30%–75% diameter stenosis. Subjects  were randomized to statin (fluvastatin) or placebo for 2.5  years and the primary end-point was a change in the  minimum lumen diameter as assessed by quantitative  coronary angiography. Marian et al.53 studied the response  to statin therapy according to ACE insertion/deletion (I/D)  genotype in the LCAS population. The subjects with DD, ID,  or II genotypes achieved reductions of 31%, 25%, and 21%,  respectively. There was a significant genotype-by-treatment  interaction (p=0.005). A similar result was obtained for  reduction in total cholesterol. Subjects with the DD  genotype also had a higher rate of regression and a lower  rate of progression than subjects with the other 2 genotypes.  

The effect of ACE inhibition on CAD progression was the subject of the Quinapril Ischemic Events Trial (QUIET). This  study showed that quinapril had only a slight effect on the  progression of CAD.54,55 However, in patients with LDL-cholesterol  levels >130 mg/dl, there was significantly less  progression in the quinapril group. Thus, the rapid  progression of disease seen in patients given a placebo with  higher LDL-cholesterol levels did not occur in patients  treated with quinapril. As in the TREND study,56 ACE  inhibitors appeared to have greater efficacy in patients with  higher LDL-cholesterol levels.  

Angiotensin-converting enzyme inhibitors are beneficial  in a variety of clinical situations, such as hypertension,  diabetes and congestive heart failure. Recent long-term  studies with ACE inhibitors in patients with decreased left  ventricular function 57–60 have shown a decrease in cardiac  ischemic events and/or a need for revascularization. One  pathogenic factor common to both heart failure and  ischemic heart disease is endothelial damage or activation,  which may explain the reduction in ischemic events seen  in these trials. More so, other clinical studies such as the  Heart Outcomes Prevention Evaluation (HOPE) trial61 have  further confirmed the benefit of reducing vascular events  and death even in patients with normal ventricular function  and normal blood pressure with pre-existing vascular or  coronary disease. The study to evaluate carotid ultrasound  changes in patients treated with ramipril and vitamin E  (SECURE) trial, a substudy of the HOPE trial, demonstrated  the beneficial effect of ramipril in preventing progression  of carotid atherosclerosis.62 Similarly, irbesartan, an AT1  receptor blocker, has been shown to regulate markers of  inflammation in patients with premature atherosclerosis;  this may retard the inflammatory process seen in  atherosclerosis.63 These findings suggest the potential role  of RAS in the development and progression of  atherosclerosis.  

No large randomized study has yet examined the  hypothesis of whether treatment by modulation of RAS  with drugs (ACE inhibitors or AT1 blockers) combined with  lipid-lowering drugs exerts additive or incremental benefits.  The ongoing randomized trial may shed light in this  direction.64 

Summary  

Hypertension and hypercholesterolemia, two major risk  factors for atherosclerotic disease, frequently coexist in  patients with hypertension and CAD. Data from clinical  studies suggest the existence of lipoprotein–neurohormonal  interactions that may adversely affect vascular structure  and reactivity. Data from preclinical studies suggest that RAS may be upregulated by abnormal lipids, most likely via  production of ox-LDL. On the other hand, activation of RAS  leads to release of ROS and transcriptional upregulation of  LDL and ox-LDL uptake in macrophages, smooth muscle  cells and endothelial cells. These findings extend our  understanding of the interplay among risk factors to  synergistically increase cardiovascular risk, and of the anti-atherosclerotic  effects of local ACE inhibition to reduce  cardiovascular risk. Trials aimed at modifying RAS along  with drugs lowering total- and LDL-cholesterol levels and  inhibitors of oxidative modification of LDL-cholesterol will  address the clinical relevance of this biological interaction. 

Correspondence:
Dr JL Mehta, 
Stebbins Chair in Cardiology, 
Professor of  Internal Medicine and Physiology, 
Director, Division of Cardiovascular  Medicine, 
University of Arkansas for Medical Sciences, 
4301 W Markham St,  Slot 532, Little Rock, 
AR 72205,USA. 
e-mail: MehtaJL@UAMS.edu

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