Number 22, 2004
Endothelial Dysfunction

Treatment options for endothelial dysfunction

Back to the Summary

Stephan von Haehling
Department of Clinical Cardiology, National Heart & Lung Institute, Imperial College School of Medicine, London, UK
Correspondence: Department of Clinical Cardiology, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, UK.
Tel: +44 2073518127, fax: +44 2073518733, e-mail: stephan.von.haehling@web.de

Introduction
Far from being inert, the vascular endothelium is an important source of mediators, which act predominantly in a paracrine fashion. These mediators maintain an antithrombotic surface, regulate vascular tone, modulate inflammatory responses, and inhibit proliferation of vascular smooth muscle cells [1]. The most important such mediator is nitric oxide, which is constitutively produced by endothelial nitric oxide synthase (eNOS). In addition, the endothelium expresses angiotensin-converting enzyme, which converts angiotensin I into the potent vasoconstrictor, angiotensin II. Normally, the production of vasoactive substances favors vasodilation; endothelial dysfunction has, therefore, widespread consequences. The condition is seen in different chronic illnesses, such as hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, and certain inflammatory diseases. Indeed, endothelial dysfunction appears to be a useful marker of early stages of various cardiovascular illnesses [2]. However, this perturbation has also been reported in normotensive individuals who merely have a family history of cardiovascular risk factors [3]. It has therefore been suggested that the onset of endothelial dysfunction may precede the development of clinically evident vascular disease in many cases [4].
Several factors contribute to a lack of nitric oxide in endothelial dysfunction. Importantly, the increased production of reactive oxygen species, such as superoxide anion, enhances nitric oxide breakdown. Achieving an increase in the production of nitric oxide and/or reducing the amount of reactive oxygen species in the endothelium appears to be a promising approach to treat endothelial dysfunction. However, other features may also be important. The expected result from such treatment would be a decrease in the number of clinical events. This review will focus on 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and angiotensin-converting enzyme (ACE) inhibitors. Several other substances have also proven beneficial in diseases that are accompanied by endothelial dysfunction.

Statins
Statins were originally designed to decrease plasma cholesterol concentrations. Five different statins are currently available, and the development of new substances is well under way. Strong and consistent evidence suggests that decreasing plasma low-density lipoprotein (LDL) concentrations alone by means of diet and plasma apheresis improves endothelial function [5,6]. Statin treatment consistently reduces cardiovascular risk [7,8] and reverses endothelial dysfunction [9,10]. Indeed, a reduction in recurrent coronary events has been observed as early as 16 weeks after the initiation of treatment [11], and it appears that these beneficial effects are independent of cholesterol decreasing activity [12].
These so-called pleiotropic effects of statins have been the subject of considerable research over recent years. Some effects are attributable to the inhibition of cholesterol biosynthesis, because substrates downstream from mevalonate in the synthesis cascade supply a number of different metabolic pathways (Figure 1) [13]. One such substrate is geranylgeranyl-pyrophosphate, which serves as a lipid attachment to Rho (Figure 2). This guanosine triphosphate-binding protein coordinates a number of specific cellular responses by interacting with downstream targets [14], and it is involved in stress fiber formation [15], monocyte adhesion, and monocyte transmigration through the endothelium [16,17]. Other mechanisms of statin action are less well understood, although these effects are likely to improve endothelial function via direct and indirect mechanisms (Figure 2). Lovastatin and simvastatin, for example, have been shown to induce eNOS gene transcription in human endothelial cells [18]. Interestingly, pravastatin improved endothelial function in monkeys at doses that do not decrease plasma LDL concentrations [19]. In this study, 32 cynomolgus monkeys were fed an atherogenic diet for 2 years, followed by a 2-year treatment phase in which they were fed a lipid-decreasing diet containing (n=14) or not containing (n=18) pravastatin. Coronary arteries of those monkeys treated with pravastatin dilated (103%), whereas those of control monkeys constricted (22%, P <0.05), in response to acetylcholine. Pravastatin has also been shown to increase the bioavailability of nitric oxide in atherosclerotic arterial walls [19], and it activates eNOS independently of its cholesterol-decreasing features [20].

Some antioxidant properties of statins have recently been documented. The two most likely sources of superoxide anion are mitochondria and immune cells, although the formation of uric acid also yields this reactive oxygen species (Figure 2) [21]. A diversity of antioxidant systems, such as superoxide dismutase and catalase, counteract the continuous generation of reactive oxygen species. Atorvastatin has recently been shown to upregulate the expression of catalase at the mRNA and protein levels in cultured rat aortic vascular smooth muscle cells [22]. However, the activity of superoxide dismutase was unaffected [22]. In this study, both angiotensin II-induced and epidermal growth factor-induced production of reactive oxygen species were downregulated [22]. These mechanisms may therefore contribute to the vasoprotective effects of statins. However, the pathways involved may still be indirect [23]. Statins also appear to be involved in an enhancement of neovascularization. Indeed, simvastatin has been shown to augment the circulating pool of bone marrow-derived endothelial progenitor cells [24].
Statin-mediated effects on the abundance of caveolin also appear to be involved in improving endothelial function. Caveolin is a marker protein of specific cell membrane invaginations (caveolae), which display the greatest cellular eNOS activity (Figure 2). Caveolin appears to interact directly with eNOS [25], and it inhibits the production of nitric oxide. Two recent studies have shown that both atorvastatin and the new substance, rosuvastatin, decrease the expression of caveolin, which ultimately leads to an increased production of nitric oxide [26,27]. Indeed, treatment with rosuvastatin for 2 weeks decreased the expression of aortic caveolin protein in apolipoprotein E-deficient mice by 2.0-fold as compared with control mice [27].
Most recently, statin-mediated anti-inflammatory effects have been observed. Simvastatin pretreatment, for example, inhibited Staphylococcus aureus-induced leukocyte rolling and adherence, as assessed by intravital microscopy in the rat mesenteric circulation [28]. Leukocyte transmigration was also significantly decreased by such treatment [28]. Another study found that pravastatin decreases the concentrations of the acute-phase reactant C-reactive protein after myocardial infarction and in patients with hypercholesterolemia [29]. As the proinflammatory cytokine, tumor necrosis factor-, is known to worsen endothelial dysfunction, it is interesting to note that lovastatin has been demonstrated to inhibit the induction of this and other proinflammatory substances in macrophages [30]. The stimulus for production of tumor necrosis factor- remains a matter of debate, but it seems that bacterial lipopolysaccharide has a significant role [31,32].

Angiotensin-converting enzyme inhibitors
Angiotensins are peptides derived from their precursor, angiotensinogen. The classic pathway of angiotensin synthesis includes a reaction catalyzed by ACE, although angiotensin II, the principal effector of the system, can also be synthesized independently of this enzyme (Figure 3) [33]. Most actions of angiotensin II support or increase arterial blood pressure and maintain glomerular filtration. Vasoconstriction, mediated by this peptide, occurs within seconds [33]. Other actions of angiotensin II, such as vascular growth and ventricular hypertrophy, take days or weeks to occur [34].

In addition to their established efficacy in decreasing blood pressure, ACE inhibitors have the broadest impact of any drug in cardiovascular medicine, reducing the risk of death, myocardial infarction, stroke, diabetes mellitus, and renal impairment [35]. In large outcome trials, ACE inhibition has been documented to reduce cardiovascular events in patients with coronary artery disease, heart failure, and related cardiovascular pathologies [3640]. Similarly, ACE inhibitors are known to improve endothelial function. This was shown, for example, in a prospective, randomized, parallel group study [41]. Endothelial function was assessed in a population of 168 patients with hypertension, before and after 6 months of treatment. Patients were randomly assigned to receive nifedipine (n=28), amlodipine (n=28), atenolol (n=29, nebivolol (n=28), telmisartan (n=29), or perindopril (n=28). All treatments reduced blood pressure to a similar extent as compared with healthy control individuals (n=40), but flow-mediated dilatation was increased only in the perindopril group (to 6.42.4%) as compared with baseline (5.12% to 6.42.4%) and the other treatment regimens (1.52.1%; P <0.01), without modifying the response to glyceryl trinitrate. After perindopril treatment, the endothelium-dependent vasodilatation in patients with hypertension was no longer different from flow-mediated dilatation in normotensive individuals.
Another double-blind, randomized, placebo-controlled study compared the effect of quinapril 40mg once daily with that of placebo, in 105 normotensive patients with coronary artery disease [42]. Using quantitative angiography, it could be demonstrated that the quinapril group showed a significant improvement in coronary artery diameter in response to incremental concentrations of acetylcholine (quinapril compared with placebo: 4.53% compared with 0.13% at 10^6 mol/L; 123% compared with 13% at 10^4 mol/L; P=0.002) [42].
Several mechanisms may contribute to the effect of ACE inhibitors and angiotensin receptor blockade on endothelial function. Indeed, angiotensin II increases the production of reactive oxygen species and hence the inactivation of nitric oxide [43]. The reason for the increase in oxidative stress is the induction of nicotinamide adenine dinucleotide phosphate oxidase activity [44]. The generation of reactive oxygen species also has a crucial role in promoting atherosclerosis by different mechanisms, such as oxidation of LDL cholesterol and upregulation of leukocyte adhesion molecules [4,45]. Besides reducing oxidative stress, ACE inhibition leads to a decrease in bradykinin breakdown, which in turn stimulates the production of nitric oxide (Figure 3) [43]. The balance between angiotensin II and nitric oxide has been suggested as a major determinant of endothelial and vascular phenotype [4].

Conclusions
Endothelial dysfunction has been recognized as a major clinical syndrome accompanying and worsening many cardiovascular diseases. Several drugs have been shown to improve endothelial function in such conditions, although this effect is currently only a side effect of treating the underlying disorder. It is tempting to speculate that the endothelium may be a direct target for future therapeutic interventions. ACE inhibitors have already been shown to improve endothelial function in patients with cardiovascular diseases [41,42]. Statins may also prove effective in this setting [46], although their potential to decrease plasma cholesterol concentrations is not always wanted. Indeed, patients with chronic heart failure suffer from endothelial dysfunction, but low plasma LDL concentrations appear to correlate with poor outcome [47]. The reason for this may lie in the fact that cholesterol potentially inactivates the activity of bacterial lipopolysaccharide in the circulation, which normally triggers the production of tumor necrosis factor- [47]. Therefore, large-scale trials are needed to establish the right doses in the right patients. This implies that very low doses of statins could still yield their beneficial pleiotropic effects without decreasing plasma cholesterol.

Summary
Endothelial dysfunction plays a significant part in various cardiovascular diseases. Therapeutic approaches to treat this perturbation have so far mainly dealt with the underlying disorder, and treatment of the endothelium was merely a side effect. This is true for ACE inhibitors, which have proven beneficial in this setting. Statins are of particular interest, because these substances counterbalance different parts of this condition. Future therapies will target the endothelium directly, in the hope that this will yield a reduction in clinical events.

Back to the Summary

REFERENCES

Back to the Summary