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Noncholesterol-lowering effects of statins

Posted on: Friday, 24 October 2003, 06:00 CDT

Statins, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, inhibit the rate-limiting enzyme in cholesterol synthesis and lead to a significant reduction of plasma lipid concentrations. As a clear correlation exists between serum cholesterol and cardiovascular risk, statins have become increasingly important in current preventive medicine. Studies prompted by the extraordinary benefits afforded by these drugs have reported minimal changes in the vasculature of hypercholesterolemic patients when compared with clinical benefits and have led to further investigations to determine the underlying reasons for these clinical benefits. The purpose of this review is to present the wide array of systems that HMG-CoA reductase inhibitors are known to influence, which range from adverse events due to coronary artery disease, stroke risk, platelet function, endothelial function, and inflammatory effects to intracellular signaling pathways that control vascular cell migration, proliferation, and differentiation.

Introduction

Statins belong to a class of drugs known as 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Table I).1,2 As HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis, and a clear correlation has been established between elevated serum cholesterol and atherosclerotic disease, statins have allowed for many advances in the primary and secondary prevention of coronary artery disease (CAD).2 Multiple centers have analyzed angiographic studies to evaluate the changes in atherosclerotic lesions known to be associated with hypercholesterolemia, in an attempt to understand how statins affect atherosclerotic lesions and ultimately benefit patients clinically. These studies have disclosed that despite a decrease in cardiac morbidity and mortality, the actual physical changes in the vessels of statin-treated patients were minimal in comparison.2-4 This discovery prompted much of the current research exploring the noncholesterol-lowering effects of statins.

Through this work, it has been shown that statins not only affect basic cellular functions, including smooth muscle cell (SMC) proliferation, SMC migration, and endothelial cell dysfunction, but also are critically involved in improved outcome from acute coronary syndromes and stroke prevention (Table II). Research focused on statins and the scope of their effect has also led to a better understanding regarding the different mechanisms by which they function.

Statins are now known to work also in cell-signaling pathways independent of the cholesterol synthesis pathway or mevalonate pathway, the inhibition of which brought them to the forefront of medicine. These theories are based on studies in which the addition of mevalonate does not reverse all effects of statin therapy. Mevalonate is the product of HMG-CoA reductase (Figure 1). When a cell is exposed to one of the statins, the function of this enzyme is inhibited, and therefore, mevalonate, and the isoprenoids it normally creates, are not produced. The alterations in cell function that follow lead to a majority of the effects seen with statin therapy. Many of the results of statin therapy can be reversed when the cells are coincubated with mevalonate, because the downstream products of mevalonate are then replaced.

Table I. Statins: cholesterol-lowering effect.

Table II. Statins: noncholesterol-lowering effect.

Figure 1. This diagram represents the mevalonate/cholesterol synthesis pathway. HMG-CoA reductase is the rate-limiting enzyme of this pathway. Mevalonate, the product of this enzyme, primarily leads to the production of cholesterol. In addition, mevalonate produces isoprenoids (FPP and GGPP), which activate various cellular proteins (Ras and Rho) and enable them to carry out their functions.

Following is a review of the current literature regarding the noncholesterol-lowering effects of statins. The clinical benefits of statin therapy are presented first, followed by a discussion of the biochemistry of the cellular and molecular functions they affect.

Clinical Section

Cardiovascular Events

Statin therapy is known to cause regression of atherosclerotic plaque, which imparts certain clinical benefits.1 For example, the Post Coronary Artery Bypass Graft (Post CABG) Trial showed that in patients who underwent cardiac revascularization, lovastatin therapy reduced plaque progression by one third compared to untreated patients.5 Consistent with this concept, Vaughan et al2 determined that the frequency of plaque regression was doubled with statin therapy when compared with controls. Other important markers of atherosclerosis, including accumulation of cholesterol in the aorta and aortic weight, were decreased by simvastatin therapy as well.6

The Scandinavian Simvastatin Survival Study (4S) showed, for the first time, that cholesterol-lowering treatment decreases all-cause mortality in patients with angina pectoris or myocardial infarction (MI).7 At the 5-year follow-up, the all-cause mortality rate was decreased by 30%, the major coronary event rate by 34%, and the coronary death rate by 42%.7 The dramatic results of this study led to the West of Scotland Coronary Prevention Study (WOSCOPS), a primary prevention study that showed pravastatin therapy reduced nonfatal MI or death from CAD significantly by 31%.8

Consistent with these studies was the Cholesterol and Recurrent Events (CARE) Trial, which showed that pravastatin reduced fatal coronary events or nonfatal MI rates by 24% and decreased the need for CABG by 26%.9 Pravastatin also reduced the risk of recurrent coronary events in patients who previously had an MI.10 The CARE Trial further demonstrated that women treated for at least 1 year with statins had a reduction in risk for coronary events and stroke.9

Statins not only reduced morbidity and mortality from CAD but also increased survival in the setting of both hypercholesterolemia and normocholesterolemia.2 This finding suggests that this class of drugs works through some mechanism other than just lowering cholesterol. In addition, statins also reduced sudden death by an order of magnitude similar to that of other cardiovascular events, and this reduction is suggested to be due to a decrease in plaque rupture and acute cardiac ischemia.2

Cerebrovascular Disease

Although the role of cholesterol in the pathogenesis of CAD is well established, a direct relationship between plasma cholesterol concentrations and independent stroke risk is not as clear; however, some important relationships between cerebrovascular disease and statin therapy have been observed.11 For example, statins have shown reversal of carotid intimal-medial thickening.6 The CARE and 4S studies showed that pravastatin reduced the stroke rate by 31%.9,12 Two separate meta-analyses have also shown an approximate 30% reduction in stroke risk with statin therapy.13,14

Several studies have examined the potential mechanisms by which statins are protective against cerebrovascular events. Recent studies on mice demonstrated that prophylactic treatment with statins for 2 weeks resulted in 25% to 30% higher cerebral blood flow and 50% smaller cerebral infarct sizes after middle cerebral artery (MCA) occlusion.15 Similar results were demonstrated by Endres et al,16 who showed that the decrease in infarct size was time-dependent, the effect being greater for mice treated for 14 days compared to 3 days. Additionally, this effect was not uniform for all statins, simvastatin conferring a greater protection against stroke than lovastatin.

In addition to increasing cerebral blood flow and decreasing infarct size, statins also have potentially limited the impact of platelet and white blood cell accumulation on tissue viability after ischemia.16 Statins are believed to lead to these protective effects by upregulating endothelial nitric oxide synthetase (eNOS) expression and activity.16,17

Plaque Rupture

Atherogenesis begins with accumulation of low-density lipoprotein (LDL) cholesterol in the endothelial space of blood vessels, followed by its oxidation.18 After this process, chemotactic factors that attract leukocytes to the vessel wall are released.18 The monocytes/macrophages drawn to the vessel wall are believed to induce plaque rupture because they produce enzymes, such as matrix metalloproteinases (MMPs), which weaken the plaque's fibrous cap and lead to rupture.19 In addition to these enzymes, macrophages also produce intimal tissue factor (TF), a potent procoagulant known to induce thrombosis.20 Statin therapy leads to a reduction in the number of macrophages that interact with atherosclerotic plaque in primates.3 Fewer macrophages lead to a decrease in MMPs and TF, thereby likely reducing the incidence of plaque rupture.

Pathological studies of acute coronary syndromes have reported that the erosion or rupture of coronary plaque followed by superimposed thrombosis and vasospasm is the principal mechanism that leads to ischemia.21 Plaque content is a major prognostic factor for plaque stability. Histologic studies of ruptured plaques reinforce the concept that a plaque with a high lipid content is more unstable and prone to rupture. Ruptured lesions contained a soft lipid-rich core, covered by a thin cap of fibrous tissue infiltrated with foam cells. A hypothesis devised by Zhao et al22 proposed that statins increase plaque stability by decreas\ing the lipid content of vulnerable lipid-rich lesions, which then causes the lesions to regress. Plaque regression was demonstrated by comparing, by means of magnetic resonance imaging (MRI), the carotid arteries of patients treated with statins versus a comparable, untreated group. In another study, patients treated with statins had their coronary lesions stabilized, which led to fewer clinical events.23

Platelet Function

Activated platelets have a critical role in acute coronary syndromes through the release of factors involved in development of platelet recruitment, cell aggregation, and thrombosis.24,25 Platelets can be activated in many ways, including through hemostatic factors such as thrombin, adenosine diphosphate (ADP), and proinflammatory stimuli [eg, interleukin-1 (IL-1) and interferon- [gamma]].26

Two of the factors released by activated platelets, ADP and adenosine triphosphate (ATP), induce locomotive activity in neutrophils.27 Additionally, ADP induces granule release from platelets and increases thromboxane A^sub 2^ (TxA^sub 2^) production, which is associated with vasoconstriction. Statins are known to decrease platelet aggregation and decrease TxA^sub 2^ metabolite excretion.28 The latter is achieved through partial inhibition of the ADP and ATP release by activated platelets.29

Prostaglandin F2-like compounds increase platelet activity and are known to be SMC mitogens.30 These compounds can be formed nonenzymatically by free radical attack of arachidonic acid in cell membranes. These free radicals are formed by a process involving oxidation. This is a major point, because patients with atherosclerotic disease have increased oxidant tone. Statins decrease platelet activity by exerting antioxidant effects.29

Thrombosis

Hypercholesterolemia is associated with an enhanced thrombotic state and a reduction in fibrinolysis.31 When patients are treated with statins, an antithrombotic effect and an increase in fibrinolysis occur. Although statins do not depress lipoprotein (Lp) levels, these drugs do ameliorate the prothrombotic state associated with simultaneously elevated Lp and LDL.32 Additionally, increased cholesterol levels are associated with increased platelet-dependent thrombin generation, and pravastatin therapy normalizes this thrombin production.33

Statins also decrease respiratory burst activity of neutrophils when coincubated with thrombin.29 This point is important because neutrophil respiratory burst activity causes a decrease in endothelial cell function and a depression in the antithrombotic nature of the endothelium.34 The depression of respiratory burst activity occurs via a nonmevalonate-dependent pathway.

Endothelial Dysfunction

Statins lead to an improvement of coronary vasomotor function by decreasing endothelial dysfunction in several ways. One mechanism appears to be through a decrease in LDL cholesterol, which leads to a decrease in vasospasm.17 Another way statins help the endothelium to be thromboresistant and vasodilatory is potentially due to their ability to increase eNOS expression and activity through inhibition of the intracellular signaling protein Rho.17 eNOS catalyzes the reaction that leads to production of endothelial nitric oxide (NO), which mediates vascular relaxation and inhibits platelet aggregation, vascular SMC proliferation, and endothelial-leukocyte interactions.35-37 Impaired synthesis, release, and activity of endothelial NO are important characteristics of endothelial dysfunction.17

Hypercholesterolemia is known to cause endothelial dysfunction.17,38 When the condition is treated, an associated decrease is present in oxidative stress.39 A reduction in oxidative stress leads to a decrease in the down-regulation of NO by free radicals.39 Martinez-Gonzalez et al38 reported that native LDL (nLDL) cholesterol levels greater than 180 mg/dL are associated with decreased eNOS messenger ribonucleic acid (mRNA) and protein expression, at a transcriptional level. Simvastatin was reported to inhibit this reaction, in a dose-dependent manner. Mevalonate was able to abrogate this effect, showing dependence on the mevalonate pathway.38

Additionally, statins benefit the endothelium through inhibition of the expression of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen.17 This finding was reinforced by Williams et al,4 who reported that the vessels of pravastatin-treated monkeys had better vasodilation than control subjects. Finally, statins induce endothelial-dependent relaxation by inhibition of the production of reactive oxygen species (ROS).17 The mechanism for this action is described in greater detail in the basic science section where guanosine triphosphate-binding proteinases (GTPases) are discussed.

Antiinflammatory Activity

Development of atherosclerosis is similar to an inflammatory response, which requires the recruitment and accumulation of leukocytes.40 Consistent with this concept is that atherosclerotic plaque express increased amounts of monocyte chemoattractant protein- 1 (MCP-1), interleukin-6 (IL-6), and interleukin-8 (IL-8), all of which are known inflammatory agents.41 MCP-1, secreted by vascular cells and activated leukocytes, is a chemotactic protein important for drawing leukocytes and granulocytes to the areas in which vascular lesions form.41 IL-6 is a pleiotropic cytokine and mediator of the acute-phase response, and exerts a broad range of effects on diverse immune cells.42 IL-8 regulates the migration of neutrophils and vascular endothelial cells.41

The antiinflammatory effects of statins have been noted both in vitro and in vivo. Rezaie-Majd et al41 demonstrated that simvastatin decreased serum concentrations of MCP-1, IL-6, and IL-8 in hypercholesterolemic patients. The drug also was reported to reduce mRNA of each of these 3 factors in peripheral blood mononuclear cells, characteristically elevated in patients with hypercholesterolemia. Additionally, human umbilical vein endothelial cells, which generally secrete MCP-1, IL-6, and IL-8, demonstrated a decrease in expression for all 3 factors following statin therapy. Statins also have been reported to inhibit nuclear factor kB, which regulates the expression of many cytokines including MCP-1, IL-6, and IL-8.43

Sukhova et al3 studied the effects of statins on atheroma in nonhuman primates. Pravastatin-treated animals expressed decreased vascular-cell adhesion molecule-1 (VCAM-1); interleukin beta-1 (IL- [beta]1), which increases VCAM production; and macrophages, which interact with atheroma.3 Statin-treated cells also expressed reduced C-reactive protein (CRP), a known marker of inflammation associated with increased cardiovascular risk.3,44 Ridker et al44 reported that pravastatin therapy reduced median CRP levels significantly in 472 patients who survived an MI.

Basophils are major proinflammatory effector cells.45 Majlesi et al45 discovered that cerivastatin and atorvastatin lead to the following: (1) a decrease in histamine release in a dose-dependent manner by basophils when undergoing immunoglobulin E (IgE)- dependent stimulation, and (2) suppression of IL-3-induced differentiation of basophils and inhibition of IgE-dependent up- regulation of the basophil-activation antigen CD203c. All these effects were reversed with addition of mevalonate, which suggests dependence on the mevalonate pathway.

Sparrow et al6 examined this effect by using simvastatin in a well-established murine model for inflammation (carrageenan-induced foot pad edema). This model involves a subplantar injection of carrageenan that induces footpad swelling, characterized as an acute inflammatory response and marked by an influx of polymorphonuclear leukocytes (PMLs).6 Inhibition of the edema indicates antiinflammatory action. When mice are treated with Indomethacin, an established antiinflammatory agent, before the injection of carrageenan, footpad edema was inhibited.6 Oral administration of simvastatin resulted in a similar effect. In other studies, simvastatin was also reported to block the influx of PMLs in cardiac muscle after ischemia and reperfusion.46 Similar data were published by Williams et al,4 who reported that pravastatin-treated monkeys had fewer macrophages in the intima and media of their vessels than control groups. These studies indicate statins exert antiinflammatory activity acutely (4 hours).6 This effect is not secondary to a decrease in cholesterol alone, because a reduction in lipids requires several days of treatment.6

Statins also inhibit chronic inflammatory activity.6 For example, long-term treatment with lovastatin blocked neuroinflammation, a response that requires T-cells, after a challenge with myelin basic protein.47 Additional studies have shown that statins block the rejection of islet transplants in animals.48 Further clinical studies have reported that simvastatin and pravastatin decrease the incidence of cardiac allograft vasculopathy in cardiac transplant patients.49,50

Vascular Procedures

Evidence exists that statins may be protective against intimal hyperplasia. In a study by Corsini et al,1 lovastatin, fluvastatin, and pravastatin were compared with regard to their effects on the vascular wall. The study showed that the lipophilic fluvastatin, but not the hydrophilic pravastatin, caused a decrease in SMC proliferation.1 Simvastatin and fluvastatin also inhibited SMC migration.51,52 Similarly pravastatin did not inhibit SMC migration. Additionally, lovastatin decreased development of intimal hyperplasia after balloon angioplasty of the femoral artery in hypercholesterolemic rabbits.53 Another interesting finding was that fluvastatin reduced catheter-induced intimal thickening in the femoral artery after puncture.1

Osteoporosis

IL-6 is known to exert profound effects on bone metabolism by regulating osteoclast and osteoblast activity.41 Scheidt-Nave et al54 revealed that the serum concentration of IL-6 is the most importan\t predictor of postmenopausal bone loss and also might be a predictor of fracture risk. As statins are known to decrease IL-6, this could partially explain their antiosteoporotic effects.41

Recent investigations suggest the mevalonate pathway has an important role in bone metabolism in vitro and in animals by way of stimulation of bone morphogenetic protein (BMP)-2, a potent regulator of osteoblast activity and differentiation.55 Statin use in the majority of observational studies was also associated with a reduced risk of hip fracture. Additionally, Skoglund et al56 reported that simvastatin improved femoral fracture healing in rats. Further studies of the skeletal effects of statins-particularly their effects on surrogate markers such as bone mass, bone turnover, and microarchitecture-are needed before they can be recommended as therapeutic agents for osteoporosis, but discoveries thus far are encouraging.

Figure 2.

This schematic of the cell demonstrates the key steps in the mevalonate pathway and the various proteins that it affects. The inhibitory effects of statins on HMG-CoA reductase and further downstream on the activation of Ras and MAPK are depicted.

Basic Science Section

A. Statins and Isoprenoids

Mevalonate is one of the products of the enzyme HMG-CoA reductase and a primary factor for production of cholesterol; however, this is not the only role it has in cell function. Mevalonate is also a precursor for a group of proteins called isoprenoids [ie, farnesyl- pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)].57 Isoprenoids are important because isoprenylation or post- translational modification is often necessary to enable other proteins to carry out their cellular functions.58 The mevalonate pathway is depicted in Figure 1.

B. Cell-Signaling Pathways

Statins exert their influence on multiple signaling pathways in the cell (Figures 1, 2). The main pathways are described below.

1. GTPases

Ras

Ras is a small, GTP-binding protein that belongs to a family of GTPases, which include 2 other subfamilies: (1) Rho and Rac; and (2) Rab.59 Ras is covalently bonded to a prenyl group essential for its function. It normally cycles between the inactive guanosine diphosphate (GDP)-bound state and active GTP-bound state.59 To be activated, Ras requires isoprenylation posttranslationally. Following activation, it attaches to farnesyl residues that allow it to be translocated from the cytoplasm to the plasma membrane, required for this protein to carry out its cellular functions.59 Ras is essential for the transmission/transduction of growth factors from receptor tyrosine kinases to the cell nucleus to promote various cell functions that include SMC proliferation and differentiation.60 When SMCs are exposed to statins, posttranslational modification of Ras does not occur and the protein is unable to function.61

In addition to a decrease in cell proliferation when Ras is inhibited, SMC migration also is depressed.60 Migration is inhibited at least partly because Ras, which is located upstream of mitogen- activated protein kinase (MAPK) is inhibited, and it leads to a decrease in MAPK activation - a pathway associated with cell migration (discussed in further detail below).

Rho

Rho is another member of the GTP-ase family of proteins.59 Rho is activated when modified after translation; however, unlike Ras, it is modified by GGPP rather than by FPP.17 Each member of the Rho family serves specific functions, including organization of the cell cytoskeleton, cell shape, motility, secretion, and proliferation.17 The activation of Rho in certain cells leads to myosin light chain phosphorylation and formation of focal adhesion complexes.17 Rho also increases the sensitivity of vascular SMCs to calcium in the setting of hypertension and coronary spasm.17 When cells are exposed to statins, the isoprenylation necessary to activate Rho is inhibited, which leads to inhibition of the cellular activities- mentioned above-that Rho proteins mediate.

Platelet-derived growth factor (PDGF), known to induce SMC proliferation, is mediated by both Rho and Ras.57 This finding was determined through experiments demonstrating that inhibition of deoxyribonucleic acid (DNA) synthesis by statins could be reversed with addition of FPP and GGPP, the isoprenoid by-products of HMG- CoA reductase that activates Ras and Rho, respectively.57 These studies suggest inhibition of Ras and Rho by statins is the predominant mechanism by which statins inhibit vascular SMC proliferation.

Rac

Rac, similar to Rho and Ras, needs to associate with the cell membrane to be activated.62 Following activation, Rac activates the nicotinamide adenine dinucleoride phosphate (NADPH) oxidase system present in SMCs.62 The NADPH oxidase system is the predominant source of ROS in the vessel wall.63 The increased release and production of ROS are thought to be major components in development of endothelial dysfunction and atherosclerosis.64 Wassmann et al62 reported that atorvastatin decreased angiotensin II- and epithelial growth factor (EGF)-induced ROS production. Additionally, atorvastatin decreased membrane-associated Rac and increased cytoplasmic Rac, which leads to a further decrease in ROS by way of reducing NADPH oxidase activity.62

2. MAPK

When proteins such as Ras are activated and attach to the cell membrane, they generate short-lived signals to the nucleus that must be propagated by other proteins.59 One of the more important of these kinases is MAPK, a member of the serine/ threonine family of proteins.59 Following its activation, MAPK is transported to the cell nucleus, where it proceeds to phosphorylate various proteins that lead to the transcription of genes and formation of certain gene regulatory proteins.59 Three distinct pathways constitute MAPK: extracellular-signal regulated kinases 1/2 (ERK 1/2), p38 kinase (p38), and c-jun N-terminal kinase (JNK).65 Through these pathways, MAPK enables cells to proliferate, differentiate, and migrate, and has been implicated in development of intimai hyperplasia.65

p44 is the phosphorylated form of MAPK encoded by the ERK-1 gene, whereas p42 is the phosphorylated form encoded by the ERK-2 gene in SMCs.60 The effect of statin therapy on these 2 subtypes of MAPK was examined by Sindermann et al.60 They demonstrated the effect of statins on 2 distinct levels: concentration of MAPK and phosphorylation of this protein. Pretreatment with Lovastatin led to a decrease in ERK-1 and ERK-2 concentration and phosphorylation. This depression in MAPK activity led to a decrease in the cellular functions it normally enhances. Inhibition studies revealed that these effects fall into 2 categories: mevalonate-dependent and mevalonate-independent. The concentration of ERK-1 and ERK-2 increased with the addition of mevalonate, however, only ERK-1 phosphorylation was affected by this protein. This implies that the effect of statins on the phosphorylation of ERK-2 is mediated via a pathway other than the one with which statins are traditionally associated.

Insulin also is known to phosphorylate or activate MAPK. It has also been reported that lovastatin decreases MAPK activation by insulin in a dose-dependent manner.66

C. Cell Cycle

The cell cycle is our basic understanding of the way in which cells replicate. G1, Synthesis or S, G2, and the Mitotic phase or M comprise the 4 phases.67 During the S phase, the cell's DNA is duplicated.67 This is a major step, because the DNA is the cell's source for mRNA, and mRNA is what is translated to ultimately define cell function.

Lovastatin was reported to arrest cells (human bladder carcinoma T24 cell line) in the G1 phase of the cell cycle after prolonged exposure, and prevent initiation of DNA replication.61 Progression through G2 was also depressed. In addition, expression of the nuclear antigen detected by Ki-67 Ab and expression of p105-2 proteins associated with proliferation-are markedly depressed by statins, another indication that statins decrease cell proliferation.

D. Growth Factors and Extracellular Matrix Proteins

PDGF

Growth factors are part of a large group of proteins responsible for stimulating cell growth and division.68 Each type of growth factor has a specific receptor it associates with and therefore the protein will stimulate only cells that express this receptor. Platelet-derived growth factor (PDGF) is categorized as a broad- specificity growth factor because it acts on a range of cells including fibroblasts, SMCs, and neuroglial cells. PDGF is relevant for vascular disease predominantly for SMC proliferation and migration, which have been implicated in restenosis after revascularization.

Simvastatin appears to work through inhibition of both farnesylation and geranylgeranylation of signal transduction proteins at various steps in the G1 phase of the cell cycle.57 PDGF- stimulated migration and cyclic strain stress-stimulated proliferation of vascular SMCs require the activity of RhoA and Rac1.57 Simvastatin strongly inhibited the membrane translocation of RhoA and PDGF-induced translocation and GTP binding of Rac1 during the late G1 phase of the cell cycle. Through these actions, Simvastatin inhibited activation of these proteins and also inhibited migration and proliferation normally mediated by Rac and Rho.

Thrombospondin-1 (TSP-1)

TSP-1 is a transient extracellular matrix glycoprotein and acute- phase reactant essentially absent in normal vessels, but it accumulates in acutely injured vessels, some early intimal hyperplastic lesions, and atherosclerotic plaque.66 On a molecular level, TSP-1 can stimulate SMC migration and proliferation through ERK and p38,69 processes implicated in development of intimal hyperplasia, a common cause of vascular reconstructive failure.66

Riessen et al70 have reported that lovastatin and simvastatin decrease the expression of TSP-1 mRNA markedly in human vascular SMCs.70 A decrease in the amount of TSP\-1 mRNA in the cell causes a decrease in the concentration of this protein, and subsequently less SMC migration.70 This effect was reversed by mevalonate, another example of a statin working through the mevalonate pathway.70

Collagen and Transforming Growth Factor [beta]-1 (TGF-[beta]1)

TGF-[beta]1 is a member of the transforming growth factor beta superfamily.68 These proteins are extracellular signaling molecules involved in a wide array of cellular functions, including regulating development and production of cell adhesion molecules, other growth factors, and extracellular molecules.68 TGF-[beta]1 is relevant to vascular surgery, because some of these kinases are involved in intracellular signaling pathways that activate MAPK and lead to SMC proliferation and migration. The 3 known categories of TGF-[beta]1 receptors are types I, II, and III. Types I and II are both transmembrane serine/threonine kinases.68 The type III receptor B- glycan regulates the association between TGF-[beta]1 and the types I and II receptors.70

After prolonged exposure (72 hours), lovastatin and simvastatin caused a marked decrease in collagen type 1 and small degree of inhibition of biglycan mRNA expression in vitro.70 This finding is relevant because with a decreased amount of biglycan in the cell, less signal transduction by the TGF-[beta]1 family of proteins occurs and their downstream effects are therefore blunted. For both drugs, inconsistent results were reported when TGF-[beta]1 was examined. TSP-1, however, is known to activate latent TGF-[beta]1. Therefore, in the presence of statins, when less TSP-1 is transcribed in the cell, less TGF-[beta]1 also is present. Pravastatin, unlike the other 2 HMG-CoA reductase inhibitors, did not have an effect on TSP-1, collagen type 1, biglycan, or TGF- [beta]1 expression.

Conclusions

When statins were first introduced, their primary function was to treat hypercholesterolemia, a condition with a clear correlation to development of atherosclerosis and coronary artery disease. As coronary artery disease remains the leading cause of death in most developed countries, the importance of these drugs was clearly evident, with a significant decrease in cardiac deaths.1 The benefits of therapy with these agents, however, have far surpassed the expectations of cholesterol reduction alone. Effects of statins range from an impressive array of systems, including development of atherosclerosis, plaque rupture and thrombosis, platelet and endothelial function, inflammatory processes, and stroke protection to their related intracellular signaling pathways including Ras, Rho, MAPK, extracellular matrix proteins, and finally growth factors (Figure 3). Although introduced for 1 particular action, these drugs have demonstrated that their range of influence is much larger. The authors have attempted to present a comprehensive review of the wide spectrum of functions statins possess. Although so much is already known regarding this class of drugs, continued research directed at discovering their full capability is still needed. Only in this way will further clinical applications be discovered.

Figure 3. This drawing summarizes the multiple effects of statins. The important clinical, cellular, and molecular systems influenced by this class of drugs are represented.

Vasc Endovasc Surg 37:301-313, 2003

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Daphne Pierre-Paul, MD, and Vivian Gahtan, MD, New Haven, CT

From the Yale University School of Medicine, Section of Vascular Surgery, New Haven, CT

Correspondence: Vivian Gahtan, MD, Yale University School of Medicine, Section of Vascular Surgery, P.O. Box 208062, FMB 137, 333 Cedar Street, New Haven, CT 06520

E-mail: Vivian.gahtan@yale.edu

(C)2003 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, USA

Copyright Westminster Publications, Inc. Sep/Oct 2003

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