Beyond lipid-lowering: effects of statins on endothelial nitric oxide

Endothelial dysfunction is now recognised as an important process in the pathogenesis of atherosclerosis. Nitric oxide (NO) release by the endothelium regulates blood flow, inflammation and platelet aggregation, and consequently its disruption during endothelial dysfunction can decrease plaque stability and encourage the formation of atherosclerotic lesions and thrombi. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) are often utilised in the prevention of coronary heart disease due to their efficacy at lowering lipid levels. However, statins may also prevent atherosclerotic disease by non-lipid or pleiotropic effects, for example, improving endothelial function by promoting the production of NO. There are various mechanisms whereby statins may alter NO release, such as inhibiting the production of mevalonate and important isoprenoid intermediates, thereby preventing the isoprenylation of the small GTPase Rho, which negatively regulates the expression of endothelial nitric oxide synthase (eNOS). Furthermore, statins may also increase eNOS activity via post-translational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3 K/Akt) pathway and/or through an interaction with the molecular chaperone heat-shock protein 90 (HSP90). Data suggest that statins may vary in their efficacy for enhancing the release of NO, and the mechanisms dictating these differences are not yet clear. By increasing NO production, statins may interfere with atherosclerotic lesion development, stabilise plaque, inhibit platelet aggregation, improve blood flow and protect against ischaemia. Therefore, the ability of statins to improve endothelial function through the release of NO may partially account for their beneficial effects at reducing the incidence of cardiovascular events.     

Statins and the Response to Myocardial Injury

The benefits of long-term statin (HMG-CoA reductase inhibitor) treatment for preventing coronary events have been well documented in several large-scale prospective clinical trials. By influencing the determinants of myocardial injury, statins may produce direct cardioprotective effects in the ischemic myocardium and prevent further damaging recurrent events. Although not proven fully in a clinical setting, cholesterol-independent or 'pleiotropic' effects of statins are thought to protect against myocardial injury and may occur via a number of mechanisms. Endothelial dysfunction occurs early in the development of atherosclerosis and is associated with a reduction in endothelial nitric oxide (NO) production. Statins have been shown to increase the expression of endothelial NO synthase, with subsequent augmentation of NO in the vasculature. Statins have also been reported to have anti-inflammatory effects, reducing the release of cytokines and chemokines, decreasing the expression of pro-inflammatory cell adhesion molecules, and reducing the accumulation of neutrophils in myocardial tissue following ischemia and reperfusion. Indeed, the role of statins in reducing infarct size is supported by data from a number of preclinical studies. Statin treatment, administered at the onset of reperfusion, has been shown to reduce infarct size by approximately 50% following ischemia in various animal models, and this may be an NO-dependent effect. Randomized clinical trials have indicated that early initiation of statin treatment is associated with a reduction in both the rate of recurrence of cardiovascular events and death in patients with acute coronary syndrome. In addition, decreased rates of myocardial infarction and mortality were demonstrated in several retrospective studies where statin treatment was administered before an interventional procedure. There is a need for further clinical trials to fully elucidate the importance of pre-procedural statin therapy and to determine the extent and mechanisms by which statins exert their cardioprotective effects.     

Therapeutic strategies targeting endothelial function in humans: clinical implications

Persistent oxidative stress in the vascular wall may lead to endothelial dysfunction, a pathological process widely implicated in the morbidities observed in a spectrum of cardiovascular disease. The production of reactive oxygen species (ROS) is regulated by various oxidase enzymes and mitochondrial electron transport mechanisms. Nitric oxide (NO) is a key mediator of endothelial function via its effect on endothelium dependent vascular relaxation. Therapeutic interventions aimed to increase NO bioavailability in the vasculature may improve the long term cardiovascular outcome for healthy individuals, high-risk subjects, and patients with advanced atherosclerosis. Current therapeutic strategies focus on enhancing synthesis or lowering oxidative inactivation of NO in human vasculature. Of the available therapeutic agents, angiotensin converting enzyme inhibitors and statins have shown most promise at improving endothelial function and cardiovascular outcome after long term administration. Other therapeutic approaches may also be useful towards improving endothelial dysfunction. These strategies include targeting NO synthesis by modulation of endothelial nitric oxide synthase (eNOS) coupling, such as folates and tetrahydrobiopterin. Evidence for the benefits of gene therapy to improve endothelial function is also emerging. However, the long term direct clinical benefit of these strategies aimed to improve endothelial function still remains unclear.     

Statins, nitric oxide and neovascularization

Several landmark clinical trials suggest that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have additional cardiovascular protective activity that may function independently of their ability to lower serum cholesterol. The cardiovascular protective effects of statins are partly caused by the activation of postnatal neovascularization. At therapeutic doses, statins promote proliferation, migration and survival of endothelial cells, induce mobilization and differentiation of bone marrow-derived endothelial progenitor cells by stimulating the serine/threonine protein kinase Akt (also known as protein kinase B) and nitric oxide (NO) signal pathway. However, at excessive doses, statins may decrease protein isoprenylation as well as inhibit endothelial cell growth and migration. NO is an important signaling molecule that regulates a wide range of physiological and pathological processes in different tissues. There is substantial evidence that effective neovascularization requires endothelium-derived NO. Statins have pleiotropic effects on the expression and activity of endothelial nitric oxide synthase (eNOS) and lead to improved NO bioavailability. NO plays an important role in the effects of statins on neovascularization. In this review, we focus on the effects of statins on neovascularization and highlight specific novel targets, such as endothelial progenitor cells and NO.     

Adverse balance of nitric oxide/peroxynitrite in the dysfunctional endothelium can be reversed by statins

Vascular endothelial dysfunction is a complex phenomenon that might be caused by a deficiency of nitric oxide (NO) and an overproduction of peroxynitrite (ONOO-). This study used a nanotechnological approach to monitor the in vitro effect of statins on the [NO]/[ONOO-] balance in normal and dysfunctional endothelial cells. NO and (ONOO-) were measured by electrochemical nanosensors in a single human umbilical vein endothelial cell (HUVEC) treated with atorvastatin or simvastatin for 24 hours in the presence or absence of 50 microg/mL oxidized-LDL. An imbalance between [NO]/[ONOO-] concentrations was used as an indicator of endothelial dysfunction and correlated with endothelial nitric oxide synthase (eNOS) expression. Ox-LDL induced dysfunction of the endothelium by uncoupling eNOS. NO concentration decreased from 300 +/- 12 to 146 +/- 8 nmol/L and (ONOO-) increased from 200 +/- 9 to 360 +/- 13 nmol/L. The [NO]/[ONOO-] balance decreased from 1.50 +/- 0.04 (control) to 0.40 +/- 0.03 for cells co-incubated with ox-LDL. Treatment with statins reversed eNOS uncoupling, induced by oxidized-LDL and significantly increased the [NO]/[ONOO-] balance to 1.2 +/- 0.1. These results demonstrate that statins can restore endothelial function by increasing eNOS expression, decreasing eNOS uncoupling, reducing the (ONOO-) level (nitroxidative stress), and shifting the [NO]/[ONOO-] balance towards NO.     

Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy

Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of diabetic vasculopathy. They are both powerful independent predictors of cardiovascular risk. Advances in non-invasive methodologies have led to widespread clinical investigation of these abnormalities in diabetes mellitus, generating a wealth of new knowledge concerning the mechanisms of vascular dysfunction, risk factor associations and potential treatment targets. Endothelial dysfunction primarily reflects decreased availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmography measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness may be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. The pathogenesis of endothelial dysfunction in type 2 diabetes is multifactorial, with principal contributors being oxidative stress, dyslipidaemia and hyperglycaemia. Elevated blood glucose levels drive production of reactive oxidant species (ROS) via multiple pathways, resulting in uncoupling of mitochondrial oxidative phosphorylation and endothelial NO synthase (eNOS) activity, reducing NO availability and generating further ROS. Hyperglycaemia also contributes to accelerated arterial stiffening by increasing formation of advanced glycation end-products (AGEs), which alter vessel wall structure and function. Diabetic dyslipidaemia is characterised by accumulation of triglyceride-rich lipoproteins, small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL)-cholesterol and increased postprandial free fatty acid flux. These lipid abnormalities contribute to increasing oxidative stress and may directly inhibit eNOS activity. Although lipid-regulating agents such as HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates) and fish oils are used to treat diabetic dyslipidaemia, their impact on vascular function is less clear. Studies in type 2 diabetes have yielded inconsistent results, but this may reflect sampling variation and the potential over-riding influence of oxidative stress, dysglycaemia and insulin resistance on endothelial dysfunction. Results of positive intervention trials suggest that improvement in vascular function is mediated by both lipid and non-lipid mechanisms, including anti-inflammatory, anti-oxidative and direct effects on the arterial wall. Other treatments, such as renin-angiotensin-aldosterone system antagonists, insulin sensitisers and lifestyle-based interventions, have shown beneficial effects on vascular function in type 2 diabetes. Novel approaches, targeting eNOS and AGEs, are under development, as are new lipid-regulating therapies that more effectively lower LDL-cholesterol and raise HDL-cholesterol. Combination therapy may potentially increase therapeutic efficacy and permit use of lower doses, thereby reducing the risk of adverse drug effects and interactions. Concomitant treatments that specifically target oxidative stress may also improve endothelial dysfunction in diabetes. Vascular function studies can be used to explore the therapeutic potential and mechanisms of action of new and established interventions, and provide useful surrogate measures for cardiovascular endpoints in clinical trials.     

The role of endothelial progenitor cells and statins in endothelial function: a review

Endothelial dysfunction, a well recognized marker of cardiovascular risk, is an early event in arteriosclerosis process. Diabetes mellitus, hypertension and dyslipidemia, known risk factors for coronary disease have been associated with endothelial dysfunction, which improves after the control of these factors. Statins have additional benefits on endothelial function not related to decreasing cholesterol levels, known as pleiotropic effects. Most recently it has been reported the effect of statins promoting bone marrow-derived mononuclear cells. These cells are positive for CD34 and KDR superficial markers of endothelial cellular lineage, which is consistent with the hypothesis that they constitute the endothelial progenitor cells. Circulating endothelial progenitor cells are involved in the repair process of the endothelium after endothelial-cell injury in myocardial ischemia, angina and other stressful situations. Recent studies have demonstrated an inverse relationship between the EPC count in peripheral blood and risk of developing a cardiovascular event. In addition, circulating EPC correlates with the presence of endothelial dysfunction and could play a role as a surrogate biologic marker in vascular function. The effect of statins on endothelial progenitor cells might contribute to improve endothelial function leading to a decrease in vascular risk, independently of their impact on LDL cholesterol. In this paper, we review the role of statins in EPC mobilization, its effect in endothelial function restoration and the relevance of this finding in cardiovascular risk. We also review future therapeutic implications.     

Renin–angiotensin system inhibitor and statins combination therapeutics – what have we learnt?

Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin–angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD.     

Nitric oxide therapies in vascular diseases.

Endothelial dysfunction defined as the impaired ability of vascular endothelium to stimulate vasodilation plays a key role in the development of atherosclerosis and in various pathological conditions which predispose to atherosclerosis, such as hypercholesterolemia, hypertension, type 2 diabetes, hyperhomocyst (e) inemia and chronic renal failure. The major cause of the endothelial dysfunction is decreased bioavailability of nitric oxide (NO), a potent biological vasodilator produced in vascular endothelium from L-arginine by the endothelial NO synthase (eNOS). In vascular diseases, the bioavailability of NO can be impaired by various mechanisms, including decreased NO production by eNOS, and/or enhanced NO breakdown due to increased oxidative stress. The deactivation of eNOS is often associated with elevated plasma levels of its endogenous inhibitor, N(G) N(G)-dimethyl-L-arginine (ADMA). In hypercholesterolemia, a systemic deficit of NO may also increase the levels of low density lipoproteins (LDL) by modulating its synthesis and metabolism by the liver, as suggested by recent in vivo and in vitro studies using organic NO donors. Therapeutic strategies aiming to reduce the risk of vascular diseases by increasing bioavailability of NO continue to be developed. Cholesterol-lowering drugs, statins, have been shown to improve endothelial function in patients with hypercholesterolemia and atherosclerosis. Promising results were also obtained in some, but not all, vascular diseases after treatment with antioxidant vitamins (C and E) and after administration of eNOS substrate, L-arginine, or its cofactor, tetrahydrobiopterin (BH(4)). Novel strategies, which may produce beneficial changes in the vascular endothelium, include the use of natural extracts from plant foods rich in phytochemicals.     

A Pharmacogenetics‐based Approach to Reduce Cardiovascular Mortality with the Prophylactic Use of Statins

Abstract: Nitric oxide (NO) is the main endothelial‐derived relaxation factor and plays a major role in cardiovascular homeostasis. This key signalling molecule is synthesised by a family of nitric oxide synthases (NOS), and the endothelial isoform (eNOS) is the most important for nitric oxide formation in the cardiovascular system. Cardiovascular drugs including statins increase eNOS expression and up‐regulate NO formation, and this effect may be responsible for protective, pleiotropic effects produced by statins. However, the genetic background may also affect NO formation in the cardiovascular system, and recent studies have shown that genetic polymorphisms in the eNOS gene modify endogenous NO formation and the risk of developing cardiovascular diseases. For example, cases with the CC genotype for the T^?786C polymorphism in the eNOS gene are at increased cardiovascular risk when compared with those with the TT genotype. Interestingly, pharmacogenetic studies have recently indicated that atorvastatin improves NO formation more clearly in these individuals. However, it is not known whether this polymorphism really increases cardiovascular morbidity and mortality, and whether atorvastatin or other statins attenuate the morbidity and mortality rates in cases with the CC genotype. If proved true, then statins‐induced up‐regulation of eNOS and increased NO formation could compensate for a genetic ‘disadvantage’ in cases with the CC genotype. This could be a significant advance in the prevention of cardiovascular events. It is necessary although to validate this hypothesis with clinical trials which will require a long follow‐up to assess relevant clinical events and not only surrogate biomarkers.     

Improvement of Endothelial Function by HMG-CoA Reductase Inhibitors

Endothelial dysfunction is the early and crucial state of atherosclerosis that is associated with a poor prognosis. Mechanistically, endothelial dysfunction is caused by reduced nitric oxide bioactivity. HMG-CoA reductase inhibitors (statins) effectively lower cholesterol plasma levels and profoundly decrease the cardiovascular risk of hypercholesterolemic patients. It is well established that statins improve endothelial dysfunction in those patients. The underlying mechanisms are less clear. It is thought that pleiotrophic, cholesterol-independent effects of statins such as increase of nitric oxide bioactivity and reduction of oxidative stress may contribute to the vasoprotective effects of statins. Therefore, it is speculated that statins, at least in part, improve endothelial function independent of plasma cholesterol concentrations and may thereby exert beneficial clinical effects. This notion of statins as general atheroprotective drugs has been underlined by in vitro experiments, animal studies and small clinical trials. However, large-scale clinical intervention studies are needed to confirm a positive influence of statins on endothelial dysfunction and cardiac event rates in normochlesterolemic patients. (c) 2002 Prous Science. All rights reserved.     

Endothelial nitric oxide synthase gene therapy for erectile dysfunction

Basic science research on erectile physiology has been devoted to investigating the pathogenesis of erectile dysfunction (ED) and has led to the conclusion that ED is predominately a disease of vascular origin. It is well recognized that the incidence of ED dramatically increases in men who suffer from diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Endothelial nitric oxide synthase (eNOS) is an important factor in cardiovascular homeostasis, angiogenesis, and erectile function. Given the impact of endothelial-derived nitric oxide (NO) in vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium in normal erectile physiology as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, a likely target of gene therapy for the treatment of ED is eNOS. This communication reviews the role of eNOS in erectile physiology and discusses the alterations in eNOS expression in various vascular diseases of the penis. Putative gene therapy interventions to restore eNOS expression and subsequent endothelial function may represent an exciting new therapeutic strategy for the future treatment of ED.     

内皮型一氧化氮合酶脱偶联的研究进展

血管内皮功能障碍(endothelial dysfunction)是多种心脑血管疾病的共同病理机制,其突出表现为内皮依赖性血管舒张功能障碍,主要由NO减少及氧自由基增加所致。最新研究发现,内皮型一氧化氮合酶脱偶联(eNOS uncoup ling)是导致NO水平下降和氧自由基水平升高的重要机制,是高血压、糖尿病、动脉粥样硬化等疾病中内皮功能障碍的重要原因。通过纠正eNOS脱偶联可有效改善内皮功能,有望为保护血管内皮功能提供有效途径。     

Statins decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro

Recent reports have implicated osteoprotegerin (OPG) in cardiovascular disease processes. Endothelial and smooth muscle cells produce OPG and its expression in these cells is upregulated by inflammatory mediators. Statins, which besides their lipid lowering properties have various vasculoprotective effects, have been shown to regulate OPG expression in osteoblasts. We investigated whether statins affect the expression of OPG in human endothelial and smooth muscle cells. Using an ELISA we could demonstrate that statins reduce tumor necrosis factor-alpha (TNF-alpha)-induced OPG production in cultured human endothelial cells and smooth muscle cells. Atorvastatin also downregulated interleukin-1alpha (IL-1alpha)-induced OPG production in endothelial cells. A significant reduction of TNF-alpha-induced OPG was seen when statins were used in the nanomolar range. These results were confirmed at the level of specific mRNA expression by real-time-PCR. Using LDH leakage as a marker of cell damage we show that cell viability was not affected by statins at concentrations used in our study. The effect of statins on TNF-alpha-induced OPG production was reversed by mevalonate and geranyl-geranyl pyrophosphate at the level of protein production and at the level of mRNA expression, suggesting that it was brought about by inhibition of the mevalonic acid pathway and protein prenylation. Through our results we have added OPG to the list of molecules whose TNF-alpha-induced upregulation is counteracted by statins. If such an effect is also operative in the in vivo setting, one could postulate a role for statins in the modulation of cardiovascular disease processes possibly regulated by OPG.     

The Many Roles of Statins in Ischemic Stroke

Stroke is the third leading cause of human death. Endothelial dysfunction, thrombogenesis, inflammatory and oxidative stress damage, and angiogenesis play an important role in cerebral ischemic pathogenesis and represent a target for prevention and treatment. Statins have been found to improve endothelial function, modulate thrombogenesis, attenuate inflammatory and oxidative stress damage, and facilitate angiogenesis far beyond lowering cholesterol levels. Statins have also been proved to significantly decrease cardiovascular risk and to improve clinical outcome. Could statins be the new candidate agent for the prevention and therapy in ischemic stroke? In recent years, a vast expansion in the understanding of the pathophysiology of ischemic stroke and the pleiotropic effects of statins has occurred and clinical trials involving statins for the prevention and treatment of ischemic stroke have begun. These facts force us to revisit ischemic stroke and consider new strategies for prevention and treatment. Here, we survey the important developments in the non-lipid dependent pleiotropic effects and clinical effects of statins in ischemic stroke.     

Antioxidants and endothelial nitric oxide synthesis

Oxidative stress in the vasculature has been suggested to contribute to the development of endothelial dysfunction via different mechanisms including LDL oxidation, nitric oxide (NO) scavenging, or oxidation of tetrahydrobiopterin, a critical cofactor of endothelial NO synthase (eNOS). Antioxidants may interfere with these processes and protect NO formed in the endothelium. In particular, ascorbic acid at high concentrations seems to be a prerequisite for sufficient NO bioavailability. Moreover, there is accumulating evidence that ascorbic acid improves tetrahydrobiopterin availability in the vasculature most probably via recycling oxidized tetrahydrobiopterin back to the fully reduced pterin. In addition, ascorbic acid may reduce the α-tocopheroxyl radical and may be required for beneficial vascular effects of α-tocopherol. Recent data have shown that apart from indirect protection of NO from inactivation, α-tocopherol exerts a direct stimulatory effect on eNOS activation via serine 1177 phosphorylation. This effect was amplified by ascorbic acid suggesting that both compounds may act synergistically in optimizing endothelial NO synthesis. The data obtained in cell culture and animal studies are promising, but human long-term studies are needed to determine whether the described mechanisms are active in vivo and may provide a rationale for optimizing dietary or supplementary intake of antioxidant vitamins in certain subsets of patients.

     

Efficacy of statins on sirtuin 1 and endothelial nitric oxide synthase expression: the role of sirtuin 1 gene variants in human coronary atherosclerosis

Statins are 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors and are used to reduce the risk of coronary artery disease (CAD) due to their pleiotropic effects. Recently, greater focus has been placed on the role of sirtuin 1 (SIRT1) in cardiovascular disease research. However, insufficient data exist on the relationships between statins, SIRT1 protein levels, and SIRT1 gene variants. In the present study, we investigated the effects of statins, atorvastatin and rosuvastatin, in CAD patients by analysing the associations between SIRT1 gene variants, rs7069102C>G and rs2273773C>T, and SIRT1/endothelial nitric oxide (eNOS) expression, as well as total antioxidant and oxidant status, and the oxidative stress index. SIRT1 expression was significantly higher, and eNOS expression was significantly lower in CAD patients when compared with controls. Statin treatment reduced SIRT1 expression and increased eNOS expression, similar to the levels found in the control population, independent from the studied SIRT1 gene variants. Oxidative stress parameters were significantly increased in CAD patients, and were decreased by statin treatment, demonstrating the antioxidative effects of statins on atherosclerosis. These results indicate that statin treatment could produce its protective effect on cardiovascular disease through the inhibition of SIRT1 expression. This is the first study reporting on the effect of statins, specifically atorvastatin and rosuvastatin, on SIRT1 expression in CAD patients.     

The Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

Vascular endothelial dysfunction is a complex phenomenon that is caused by an imbalance of vasodilator and vasoconstrictor factors that regulate the equilibrium-maintaining vascular tone. In the early phase of hypercholesterolemia, endothelial dysfunction precedes vascular wall lesions. One of the earliest recognizable benefits of treatment with HMG-CoA reductase inhibitors (statins) is the normalization of endothelium-dependent relaxation in hypercholesterolemia; this effect occurs before significant lowering of serum cholesterol levels. Recent insights into cellular mechanisms indicate that statins promote vasorelaxation by upregulating the expression of endothelial nitric oxide (NO) synthase, activating the phosphatidylinositide 3-kinase/Akt pathway, inhibiting superoxide anion generation and endothelin synthesis, and by anti-inflammatory effects. These effects appear to be linked to the inhibition of geranylgeranylation of small G proteins such as Rho and Rac GTPases. In this regard, statins preserve endothelial function through the improvement of NO bioavailability and the reduction of oxidative stress, thereby shifting the balance from vasoconstriction to vasodilation. This review highlights the various mechanisms underlying the vasculoprotective effects of statins, independent of their effects on cholesterol lowering.     

Benidipine, a dihydropyridine-calcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release.

Benidipine hydrochloride (benidipine), which is a long-lasting dihydropyridine calcium channel blocker, exerts antihypertensive action via inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels. In addition, benidipine is shown to restore endothelial function. However, the mechanisms whereby benidipine has protective effects on endothelium are poorly defined. Nitric oxide (NO), which is produced by endothelial NO synthase (eNOS), plays important roles in endothelial function. In this study, we examined effects of benidipine on NO production from human umbilical vein endothelial cells. Benidipine (0.3-10 microM) augmented eNOS expression and total eNOS enzymatic activities. Benidipine also promoted the production of NO and the accumulation of cGMP, a second messenger of NO. Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoproteins, induced caspase-3 activation followed by apoptosis of endothelial cells. Benidipine (0.3-10 microM) prevented lysoPC-induced caspase-3 activation, which was canceled by Nomega-nitro-L-arginine-methyl ester (L-NAME) (250-2500 microM), an inhibitor of NOS. Moreover, diethylenetetraamine NONOate (30-100 microM), a NO donor, inhibited the caspase-3 activation. These results suggested that the increase in NO production by benidipine might be involved in the inhibition of caspase induction. The direct enhancement of endothelial NO release by benidipine may be in part responsible for amelioration of endothelial dysfunction.