doi: 10.1161/hq1101.098486
© 2001 American Heart Association, Inc.
Brief Review |
Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
From the Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Dr James K. Liao, Brigham & Women’s Hospital, 221 Longwood Ave, LMRC-322, Boston, MA 02115. E-mail jliao{at}rics.bwh.harvard.edu
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Abstract |
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Abstract—— The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are potent inhibitors of cholesterol biosynthesis. Several large clinical trials have demonstrated the beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, the overall clinical benefits observed with statin therapy appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation. Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall.
Key Words: endothelium • vascular smooth muscle • platelets • atherosclerosis • inflammation
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Introduction |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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Atherosclerosis is the underlying disorder in the majority of patients with cardiovascular disease.1 Although the development of atherosclerosis is dependent on many factors and processes, a clear association has been established between elevated serum cholesterol levels and increased atherosclerotic disease.2–5 Recent large clinical trials have demonstrated that statins decrease the incidence of coronary heart disease in patients with hypercholesterolemia and atherosclerosis.6–10 Depending on the dose and the type of the statin used, LDL was decreased anywhere from 19% to 60% in response to therapy. In addition, HDL cholesterol levels were increased, and triglycerides were decreased as a result of statin therapy. These lipid effects of statins are believed to slow the progression of atherosclerosis, because atherosclerosis is mediated, in part, by the uptake of modified LDL, which eventually constitutes the lipid core of atherosclerotic lesions.11
Because serum cholesterol levels are strongly associated with coronary atherosclerotic disease,12 it has been generally assumed that cholesterol reduction by statins is the predominant, if not the only, mechanism underlying their beneficial effects in cardiovascular diseases. However, subgroup analyses of large clinical trials have challenged this notion and have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. For example, subgroup analysis of the West of Scotland Coronary Prevention (WOSCOP) and Cholesterol and Recurrent Events (CARE) studies indicates that despite comparable serum cholesterol levels among the statin-treated and placebo groups, statin-treated individuals have a significantly lower risk of coronary heart disease than do age-matched placebo-controlled individuals.8,9,13,14 Furthermore, meta-analyses of cholesterol-lowering trials suggest that the risk of myocardial infarction in individuals treated with statins is significantly lower than that in individuals treated with other cholesterol-lowering agents or modalities despite comparable reduction in serum cholesterol levels in both groups.15,16 These findings suggest that statins may have beneficial effects beyond cholesterol lowering.
Further evidence in support of the noncholesterol benefits of statin therapy is provided by angiographic trials, which have demonstrated clinical improvements with statins that far exceed changes in the size of atherosclerotic lesions. For example, in the Familial Atherosclerosis Treatment Study (FATS) trial, statin therapy with bile acid resin decreased the incidence of coronary events by 70% despite producing only a 0.7% change in lesion regression.15,17 Indeed, many of the beneficial effects of statins in the FATS trial were attributed to plaque stabilization and remodeling. However, in the recent Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) trial, statins were found to be effective in reducing recurrent ischemic events as early as 16 weeks after acute coronary ischemia.18 Although the serum LDL cholesterol was reduced by 40%, this time frame was probably too short for appreciable changes in vascular remodeling. Therefore, it is believed that some other actions of statins, particularly the improvement of endothelial function, may have contributed to these early benefits (Table).19,20
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Statins and Isoprenylated Proteins |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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By inhibiting L-mevalonic acid synthesis, statins also prevent the synthesis of other important isoprenoid intermediates of the cholesterol biosynthetic pathway, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP)21; see Figure 1. These intermediates serve as important lipid attachments for the posttranslational modification of a variety of proteins, including the
subunit of heterotrimeric G proteins, Heme-a, nuclear lamins, and the small GTP-binding protein Ras and Ras-like proteins, such as Rho, Rab, Rac, Ral, and Rap.22 Thus, protein isoprenylation permits the covalent attachment, subcellular localization, and intracellular trafficking of membrane-associated proteins. Members of the Ras and Rho GTPase family are major substrates for posttranslational modification by prenylation.22,23 Ras and Rho are small GTP-binding proteins that cycle between the inactive GDP-bound state and active GTP-bound state. In endothelial cells, Ras translocation from the cytoplasm to the plasma membrane is dependent on farnesylation, whereas Rho translocation is dependent on geranylgeranylation.24,25 Statins inhibit Ras and Rho isoprenylation, leading to the accumulation of inactive Ras and Rho in the cytoplasm. .
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Because Rho is a major target of geranylgeranylation, inhibition of Rho and its downstream target, Rho kinase, is a likely mechanism mediating some of the pleiotropic effects of statins on the vascular wall.26 Each member of the Rho family serves specific functions in terms of cell shape, motility, secretion, and proliferation, although overlapping functions between the members could be observed in overexpressed systems. The activation of Rho in Swiss 3T3 fibroblasts by extracellular ligands, such as platelet-derived lysophosphatidic acid, leads to myosin light chain phosphorylation and the formation of focal adhesion complexes.22,23,27 Indeed, Rho-associated protein kinase increases the sensitivity of vascular smooth muscle to calcium in hypertension28 and coronary spasm.29 In contrast, activation of Rac leads to the formation of lamellipodia and membrane ruffles, whereas activation of Cdc42 induces actin-rich surface protrusions called filopodia. Thus, changes in Rho-induced actin cytoskeleton can affect intracellular transport, membrane trafficking, mRNA stability, and gene transcription. Indeed, evidence suggests that inhibition of Rho isoprenylation mediates many of the cholesterol-independent effects of statins not only in vascular wall cells24,30 but also in leukocytes31 and bone.32
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Statins and Endothelial Function |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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The vascular endothelium serves as an important autocrine and paracrine organ that regulates vascular wall contractile state and cellular composition. Hypercholesterolemia impairs endothelial function, and endothelial dysfunction is one of the earliest manifestations of atherosclerosis, occurring even in the absence of angiographic evidence of disease.33,34 An important characteristic of endothelial dysfunction is the impaired synthesis, release, and activity of endothelium-derived NO. Endothelial NO has been shown to inhibit several components of the atherogenic process. For example, endothelium-derived NO mediates vascular relaxation35 and inhibits platelet aggregation,36 vascular smooth muscle proliferation,37 and endothelium-leukocyte interactions.38,39 Inactivation of NO by superoxide anion (O2·-) limits the bioavailability of NO and leads to nitrate tolerance, vasoconstriction, and hypertension.40,41
Acute plasma LDL apheresis improves endothelium-dependent vasodilatation,42 suggesting that statins could restore endothelial function, in part, by lowering serum cholesterol levels. However, in some studies with statins, restoration of endothelial function occurs before significant reduction in serum cholesterol levels,43–45 suggesting that there may be additional effects on endothelial function beyond that of cholesterol reduction. Indeed, statins increase NO bioavailability by stimulating and upregulating endothelial NO synthase (eNOS)24,46 or by decreasing oxidative stress.47 Furthermore, statins have been shown to restore eNOS activity in the presence of hypoxia48 and oxidized LDL,24 conditions that lead to endothelial dysfunction. Statins also increase the expression of tissue-type plasminogen activator49 and inhibit the expression of endothelin-1, a potent vasoconstrictor and mitogen.50 Therefore, statins exert many favorable effects on the endothelium and attenuate endothelial dysfunction in the presence of atherosclerotic risk factors.
Whereas the effects of statins on Ras and Rho isoprenylation are reversed in the presence of FPP and GGPP, respectively, the effects of statins on eNOS expression are reversed only with GGPP and not with FPP or LDL cholesterol.25 These findings are consistent with a non-cholesterol-lowering effect of statins and suggest that inhibition of Rho by statins mediates the increase in eNOS expression (Figure 2). Indeed, statins upregulate eNOS expression by prolonging eNOS mRNA half-life but not eNOS gene transcription.25 Because hypoxia, oxidized LDL, and cytokines such as tumor necrosis factor-
decrease eNOS expression by reducing eNOS mRNA stability, the ability of statins to prolong eNOS half-life may make them effective agents in counteracting conditions that downregulate eNOS expression. .
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Another potential mechanism by which statins may improve endothelial function is through their antioxidant effects. For example, statins enhance endothelium-dependent relaxation by inhibiting the production of reactive oxygen species (ROS), such as such as superoxide and hydroxy radicals, from aortas of cholesterol-fed rabbits.47 Although lipid lowering by itself can lower vascular oxidative stress,51,52 some of these antioxidant effects of statins appear to be cholesterol independent. For example, statins attenuate angiotensin II-induced free radical production in vascular smooth muscle cells (SMCs) by inhibiting Rac1-mediated NADH oxidase activity and downregulating angiotensin type 1 receptor expression.53 Because NO is scavenged by ROS, these findings indicate that the antioxidant properties of statins may also contribute to their ability to improve endothelial function.40,41
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Statins and SMC Proliferation |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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The proliferation of vascular SMCs is a central event in the pathogenesis of vascular lesions, including postangioplasty restenosis, transplant arteriosclerosis, and veinous graft occlusion.54 Recent studies have shown that statins attenuate vascular proliferative disease, such as transplant-associated arteriosclerosis.54 In contrast to atherosclerosis, transplant-associated arteriosclerosis is more of an immunologic than a lipid disorder, although hypercholesterolemia exacerbates the immunologic process.55 Inhibition of isoprenoid but not cholesterol synthesis by statins decreased platelet-derived growth factor (PDGF)-induced DNA synthesis in vascular SMCs.30,56 Treatment with statins decreased PDGF-induced retinoblastoma gene product (Rb) hyperphosphorylation and cyclin-dependent kinase (cdk)-2, cdk-4, and cdk-6 activities. This was correlated with increases in the level of the cdk inhibitor p27Kip1, without concomitant changes in p16INK4, p21Waf1, or p53 levels. These findings indicate that statins inhibit vascular SMC proliferation by arresting the cell cycle between the G1 phase-to-S phase transition. It remains to be determined whether the upregulation of p27Kip1 is responsible for the cell cycle arrest and whether there are differences between the various statins in terms of p27Kip1 upregulation.
Because the small GTP-binding proteins, Ras and Rho, require posttranslational modification for membrane localization and activity and are implicated in cell cycle regulation, they are likely targets for the direct antiproliferative vascular effects of statins. Ras can promote cell cycle progression via activation of the mitogen-activated protein kinase pathway,57 whereas Rho causes cellular proliferation possibly through destabilizing p27Kip1 protein.58 Interestingly, inhibition of vascular SMC proliferation by statins was reversed by GGPP, but not FPP or LDL cholesterol.30 Indeed, direct inhibition of Rho by Clostridium botulinum C3 transferase, which ADP-ribosylates and inactivates Rho, or by a dominant-negative Rho mutant increased p27Kip1 and inhibited Rb hyperphosphorylation and SMC proliferation after PDGF stimulation.30 Taken together, these findings indicate that Rho mediates PDGF-induced SMC proliferation and that inhibition of Rho by statins is the predominant mechanism by which statins inhibit vascular SMC proliferation.
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Statins and Platelet Function |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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Platelets play a critical role in the development of acute coronary syndromes.59 Acute thrombus formation at the site of plaque rupture and vascular injury accounts for most episodes of acute coronary syndromes.60–62 Hypercholesterolemia is associated with increases in platelet reactivity.63,64 These abnormalities are linked to increases in the cholesterol/phospholipid ratio in platelets. Other potential mechanisms include increases in thromboxane A2 biosynthesis,65 platelet
2-adrenergic receptor density,66 and platelet cytosolic calcium.67 Statins have been shown to inhibit platelet function.68–70 Potential mechanisms include a reduction in the production of thromboxane A2 and modifications in the cholesterol content of platelet membranes.71,72 The cholesterol content of platelet and erythrocyte membranes is reduced in patients undergoing statin therapy. This may lead to a decrease in the thrombogenic potential of these cells. Indeed, animal studies suggest that statin therapy inhibits platelet deposition on damaged vessels and reduces platelet thrombus formation.61,73,74 Furthermore, in vitro experiments have demonstrated that statins inhibit tissue factor expression by macrophages, thereby potentially reducing the thrombotic potential of the vascular wall.75
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Statins and Plaque Stability |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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Plaque rupture is a major cause of acute coronary syndromes.34,76–79 The atherosclerotic lesion contains highly thrombogenic materials in the lipid core that are separated from the bloodstream by a fibrous cap.80 Fissuring, erosion, and ulceration of the fibrous cap eventually leads to plaque rupture and ensuing thrombosis.78 Collagen is the main component of fibrous caps and is responsible for their tensile strength. Because macrophages are capable of degrading the collagen-containing fibrous cap, they play an important role in the development and subsequent stability of atherosclerotic plaques.81,82 Indeed, degradation of the plaque matrix appears to be most active in macrophage-rich regions.76,78 Secretion of proteolytic enzymes, such as matrix metalloproteinases (MMPs), by activated macrophages may weaken the fibrous cap, particularly at the "vulnerable" shoulder region, where the fibrous cap joins the arterial wall.83,84 Weakened fibrous caps lead to plaque instability, rupture, and ensuing thrombosis, which ultimately present as acute coronary syndromes.79,85
Lipid lowering by statins may contribute to plaque stability by reducing plaque size or by modifying the physiochemical properties of the lipid core.86,87 However, as mentioned previously, changes in plaque size by lipid lowering tend to occur over extended time and are quite minimal, as assessed by angiography. Rather, the clinical benefits from lipid lowering are probably due to decreases in macrophage accumulation in atherosclerotic lesions and inhibition of MMP production by activated macrophages.75 Indeed, statins inhibit the expression of MMPs and tissue factor by cholesterol-dependent and -independent mechanisms,75,86,88 with the cholesterol-independent or direct macrophage effects occurring at a much earlier time frame. Therefore, the plaque-stabilizing properties of statins are mediated through a combined reduction in lipids, macrophages, and MMPs.89 These effects of statins may reduce the incidence of acute coronary syndromes by lessening the propensity for plaque to rupture.
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Statins and Vascular Inflammation |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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Atherosclerosis is a complex inflammatory process that is characterized by the presence of monocytes or macrophages and T lymphocytes in the atheroma.11,90 Inflammatory cytokines secreted by these macrophages and T lymphocytes can modify endothelial function, SMC proliferation, collagen degradation, and thrombosis.79 An early step in atherogenesis involves monocyte adhesion to the endothelium and penetration into the subendothelial space.90 Recent studies suggest that statins possess anti-inflammatory properties by their ability to reduce the number of inflammatory cells in atherosclerotic plaques.71 The mechanisms have yet to be fully elucidated but may involve inhibition of adhesion molecules such as intercellular adhesion molecule-1, which are involved in the recruitment of inflammatory cells.91 Indeed, a recent study has shown that statins can suppress the inflammatory response independent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by binding directly to a novel regulatory site of the ß2 integrin, leukocyte function antigen-1, which serves as a major counterreceptor for intercellular adhesion molecule-1 on leukocytes.92 Furthermore, statins protect the ischemic myocardium by attenuating P-selectin expression and leukocyte adhesion in normocholesterolemic and diabetic animals.93–97 These cholesterol-independent effects of statins were absent in eNOS-deficient or NG-nitro-L-arginine methyl ester-treated mice, suggesting that eNOS mediated the vascular protective effects of statins.
A clinical marker of inflammation is high-sensitivity C-reactive protein (hs-CRP).98 hs-CRP is an acute-phase reactant that is produced by the liver in response to proinflammatory cytokines, such as interleukin-6, and reflects low-grade systemic inflammation.99 Elevated levels of hs-CRP have been shown to be predictive of increased risk of coronary artery disease in apparently healthy men and women.36,100–103 hs-CRP is elevated in patients with coronary artery disease, coronary ischemia, and myocardial infarction compared with normal subjects.43,104,105 Statin therapy lowers hs-CRP levels in hypercholesterolemic patients.98,106,107 In the CARE trial, statins significantly decreased plasma hs-CRP levels over a 5-year period in patients who did not experience recurrent coronary events.108,109 Similarly, an analysis of baseline and 1-year follow-up from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that hs-CRP levels were reduced in statin-treated patients who were free of acute major coronary events.98 Therefore, these studies indicate that statins are effective in decreasing systemic and vascular inflammation. However, any potential clinical benefits conferred by the lowering of hs-CRP are difficult to separate from the benefits of the lipid-lowering effects of statins without performing further clinical studies.
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Statins and Ischemic Stroke |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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An intriguing result of large clinical trials with statins is the reduction in ischemic stroke.110 Although myocardial infarction is closely associated with serum cholesterol levels, neither the Framingham Heart Study nor the Multiple Risk Factor Intervention Trial (MRFIT) demonstrated significant correlation between ischemic stroke and serum cholesterol levels.5,111 Thus, the findings of these large statin trials raise the interesting question of how a class of cholesterol-lowering agents can reduce ischemic stroke when ischemic stroke is not related to cholesterol levels. It appears likely that there are pleiotropic effects of statins that are beneficial in ischemic stroke. Some of these beneficial effects of statins in ischemic stroke may be due, in part, to their ability to upregulate eNOS expression and activity.24,46 For example, mice that were prophylactically treated with statins for up to 2 weeks had 25% to 30% higher cerebral blood flow and 50% smaller cerebral infarct sizes after cerebrovascular occlusion.26,112 No increase in cerebral blood flow or neuroprotection was observed in eNOS-deficient mice treated with statins, indicating that the upregulation of eNOS accounts for most, if not all, of the neuroprotective effects of these agents. Interestingly, treatment with statins did not affect blood pressure or heart rate before, during, or after cerebrovascular ischemia and did not alter serum cholesterol levels in mice, consistent with the cholesterol-independent neuroprotective effects of statins.
In addition to increases in cerebral blood flow, other beneficial effects of statins that have an impact on the severity of ischemic stroke are likely to occur. For example, statins attenuate P-selectin expression and leukocyte adhesion via increases in NO production in a model of cardiac ischemia and reperfusion.93,96 Others have reported that statins upregulate tissue-type plasminogen activator and downregulate plasminogen activator inhibitor-1 expression through a similar mechanism involving the inhibition of Rho geranylgeranylation.49 Thus, the absence of neuroprotection in eNOS-deficient mice emphasizes the importance of endothelium-derived NO not only in augmenting cerebral blood flow but also, potentially, in limiting the impact of platelet and white blood cell accumulation on tissue viability after ischemia. It is possible that statins may have contributed to the decrease in the incidence of ischemic strokes in clinical trials, in part, by reducing cerebral infarcts size to levels that are clinically unappreciated.
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Summary |
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TopAbstractIntroductionStatins and Isoprenylated...Statins and Endothelial FunctionStatins and SMC ProliferationStatins and Platelet FunctionStatins and Plaque StabilityStatins and Vascular...Statins and Ischemic StrokeSummaryReferences |
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Statins exert many pleiotropic effects on the vascular wall. These include beneficial effects on endothelial function and blood flow, decreasing LDL oxidation, enhancing the stability of atherosclerotic plaques, inhibiting vascular SMC proliferation and platelet aggregation, and reducing vascular inflammation (Figure 3). Recent evidence suggests that most of these effects are mediated by the inhibitory effect of statins on isoprenoid synthesis. In particular, inhibition of Rho GTPases in vascular wall cells by statins leads to increased expression of atheroprotective genes and inhibition of vascular SMC proliferation. Although the list of cellular effects of statins on the vascular wall continues to grow, it remains to be determined which, if any, of these effects accounts for the clinical benefits of statin therapy in cardiovascular disease. .
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Acknowledgments |
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The work described in this article was supported in part by the National Institutes of Health (HL-52233, HL-48743, HL-62602, and NS-10828) and the American Heart Association Bugher Foundation Award. Dr Liao is an Established Investigator of the American Heart Association. Dr Takemoto is a recipient of a Banyu-Merck Fellowship.
Received July 24, 2001; accepted August 29, 2001.
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References |
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K. I. Paraskevas, C. D. Liapis, G. Hamilton, and D. P. Mikhailidis Are Statins an Option in the Management of Abdominal Aortic Aneurysms? Vascular and Endovascular Surgery, May 1, 2008; 42(2): 128 - 134. [Abstract] [PDF]
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M. Abe, M. Matsuda, H. Kobayashi, Y. Miyata, Y. Nakayama, R. Komuro, A. Fukuhara, and I. Shimomura Effects of Statins on Adipose Tissue Inflammation: Their Inhibitory Effect on MyD88-Independent IRF3/IFN-{beta} Pathway in Macrophages Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 871 - 877. [Abstract] [Full Text] [PDF]
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S. P. Didion Chlamydophila pneumoniae and Endothelial Activation: The Smoke That Precedes the Fire of Atherosclerosis? Circ. Res., April 25, 2008; 102(8): 861 - 863. [Full Text] [PDF]
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B. Schmeck, W. Beermann, P. D. N'Guessan, A. C. Hocke, B. Opitz, J. Eitel, Q. T. Dinh, M. Witzenrath, M. Krull, N. Suttorp, et al. Simvastatin Reduces Chlamydophila pneumoniae-Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells Circ. Res., April 25, 2008; 102(8): 888 - 895. [Abstract] [Full Text] [PDF]
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 V. Kolavennu, L. Zeng, H. Peng, Y. Wang, and F. R. Danesh Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control Diabetes, March 1, 2008; 57(3): 714 - 723. [Abstract] [Full Text] [PDF]
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X. Sun and D. D. Ku Rosuvastatin provides pleiotropic protection against pulmonary hypertension, right ventricular hypertrophy, and coronary endothelial dysfunction in rats Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H801 - H809. [Abstract] [Full Text] [PDF]
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S. G. Sala, U. Munoz, F. Bartolome, F. Bermejo, and A. Martin-Requero HMG-CoA Reductase Inhibitor Simvastatin Inhibits Cell Cycle Progression at the G1/S Checkpoint in Immortalized Lymphocytes from Alzheimer's Disease Patients Independently of Cholesterol-Lowering Effects J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 352 - 359. [Abstract] [Full Text] [PDF]
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T.-M. Lee, M.-S. Lin, and N.-C. Chang Effect of pravastatin on sympathetic reinnervation in postinfarcted rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3617 - H3626. [Abstract] [Full Text] [PDF]
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P. Amarenco, L. B. Goldstein, M. Szarek, H. Sillesen, A. E. Rudolph, A. Callahan III, M. Hennerici, L. Simunovic, J. A. Zivin, K. M. A. Welch, et al. Effects of Intense Low-Density Lipoprotein Cholesterol Reduction in Patients With Stroke or Transient Ischemic Attack: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial Stroke, December 1, 2007; 38(12): 3198 - 3204. [Abstract] [Full Text] [PDF]
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 S. M. Ostrowski, B. L. Wilkinson, T. E. Golde, and G. Landreth Statins Reduce Amyloid-beta Production through Inhibition of Protein Isoprenylation J. Biol. Chem., September 14, 2007; 282(37): 26832 - 26844. [Abstract] [Full Text] [PDF]
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 C. Vlachopoulos, K. Aznaouridis, A. Dagre, C. Vasiliadou, C. Masoura, E. Stefanadi, J. Skoumas, C. Pitsavos, and C. Stefanadis Protective effect of atorvastatin on acute systemic inflammation-induced endothelial dysfunction in hypercholesterolaemic subjects Eur. Heart J., September 1, 2007; 28(17): 2102 - 2109. [Abstract] [Full Text] [PDF]
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 J. Afilalo, A. A Majdan, and M. J Eisenberg Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials Heart, August 1, 2007; 93(8): 914 - 921. [Abstract] [Full Text] [PDF]
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 S. Collot-Teixeira, J. Martin, C. McDermott-Roe, R. Poston, and J. L. McGregor CD36 and macrophages in atherosclerosis Cardiovasc Res, August 1, 2007; 75(3): 468 - 477. [Abstract] [Full Text] [PDF]
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 G. I. Boger, T. K. Rudolph, R. Maas, E. Schwedhelm, E. Dumbadze, A. Bierend, R. A. Benndorf, and R. H. Boger Asymmetric Dimethylarginine Determines the Improvement of Endothelium-Dependent Vasodilation by Simvastatin: Effect of Combination With Oral L-Arginine J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2274 - 2282. [Abstract] [Full Text] [PDF]
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M. Sugita, H. Sugita, and M. Kaneki Farnesyltransferase Inhibitor, Manumycin A, Prevents Atherosclerosis Development and Reduces Oxidative Stress in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1390 - 1395. [Abstract] [Full Text] [PDF]
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M. Yano, T. Matsumura, T. Senokuchi, N. Ishii, Y. Murata, K. Taketa, H. Motoshima, T. Taguchi, K. Sonoda, D. Kukidome, et al. Statins Activate Peroxisome Proliferator-Activated Receptor {gamma} Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase-Dependent Cyclooxygenase-2 Expression in Macrophages Circ. Res., May 25, 2007; 100(10): 1442 - 1451. [Abstract] [Full Text] [PDF]
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E. M. Tuzcu and S. J. Nicholls Statins: Targeting Inflammation by Lowering Low-Density Lipoprotein? J. Am. Coll. Cardiol., May 22, 2007; 49(20): 2010 - 2012. [Full Text] [PDF]
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 M. G. Flynn, B. K. McFarlin, and M. M. Markofski State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training American Journal of Lifestyle Medicine, May 1, 2007; 1(3): 220 - 235. [Abstract] [PDF]
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 T. Palmerini, A. Marzocchi, C. Marrozzini, L. B. Reggiani, C. Savini, G. Marinelli, R. Di Bartolomeo, and A. Branzi Preoperative C-reactive protein levels predict 9-month mortality after coronary artery bypass grafting surgery for the treatment of left main coronary artery stenosis Eur. J. Cardiothorac. Surg., April 1, 2007; 31(4): 685 - 690. [Abstract] [Full Text] [PDF]
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O. Saijonmaa, T. Nyman, and F. Fyhrquist Atorvastatin inhibits angiotensin-converting enzyme induction in differentiating human macrophages Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1917 - H1921. [Abstract] [Full Text] [PDF]
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M. Yokoyama, T. Seo, T. Park, H. Yagyu, Y. Hu, N. H. Son, A. S. Augustus, R. K. Vikramadithyan, R. Ramakrishnan, L. K. Pulawa, et al. Effects of lipoprotein lipase and statins on cholesterol uptake into heart and skeletal muscle J. Lipid Res., March 1, 2007; 48(3): 646 - 655. [Abstract] [Full Text] [PDF]
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 T. Nagaoka, T. W. Hein, A. Yoshida, and L. Kuo Simvastatin Elicits Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and Mevalonate-Rho Kinase Pathways Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 825 - 832. [Abstract] [Full Text] [PDF]
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E. S Houslay, J. Sarma, and N. G Uren The effect of intensive lipid lowering on coronary atheroma and clinical outcome Heart, February 1, 2007; 93(2): 149 - 151. [Abstract] [Full Text] [PDF]
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L. Hauck, C. Harms, D. Grothe, J. An, K. Gertz, G. Kronenberg, R. Dietz, M. Endres, and R. von Harsdorf Critical Role for FoxO3a-Dependent Regulation of p21CIP1/WAF1 in Response to Statin Signaling in Cardiac Myocytes Circ. Res., January 5, 2007; 100(1): 50 - 60. [Abstract] [Full Text] [PDF]
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S. Nakata, M. Tsutsui, H. Shimokawa, T. Yamashita, A. Tanimoto, H. Tasaki, K. Ozumi, K. Sabanai, T. Morishita, O. Suda, et al. Statin Treatment Upregulates Vascular Neuronal Nitric Oxide Synthase Through Akt/NF-{kappa}B Pathway Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 92 - 98. [Abstract] [Full Text] [PDF]
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 G. M. Howard-Alpe, J. W. Sear, and P. Foex Methods of detecting atherosclerosis in non-cardiac surgical patients; the role of biochemical markers Br. J. Anaesth., December 1, 2006; 97(6): 758 - 769. [Abstract] [Full Text] [PDF]
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 H. Xu, L. Zeng, H. Peng, S. Chen, J. Jones, T.-L. Chew, M. M. Sadeghi, Y. S. Kanwar, and F. R. Danesh HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation Am J Physiol Renal Physiol, November 1, 2006; 291(5): F995 - F1004. [Abstract] [Full Text] [PDF]
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M. Yao, R.-H. Zhou, M. Petreaca, L. Zheng, J. Shyy, and M. Martins-Green Activation of sterol regulatory element-binding proteins (SREBPs) is critical in IL-8-induced angiogenesis J. Leukoc. Biol., September 1, 2006; 80(3): 608 - 620. [Abstract] [Full Text] [PDF]
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N. Tanaka, Y. Momiyama, R. Ohmori, A. Yonemura, M. Ayaori, M. Ogura, S. Sawada, M. Kusuhara, H. Nakamura, and F. Ohsuzu Effect of atorvastatin on plasma osteopontin levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): e129 - e130. [Full Text] [PDF]
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 K. Groschel, U. Ernemann, J. B. Schulz, T. Nagele, C. Terborg, and A. Kastrup Statin Therapy at Carotid Angioplasty and Stent Placement: Effect on Procedure-related Stroke, Myocardial Infarction, and Death. Radiology, July 1, 2006; 240(1): 145 - 151. [Abstract] [Full Text] [PDF]
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 K. Sakoda, M. Yamamoto, Y. Negishi, J.K. Liao, K. Node, and Y. Izumi Simvastatin Decreases IL-6 and IL-8 Production in Epithelial Cells Journal of Dental Research, June 1, 2006; 85(6): 520 - 523. [Abstract] [Full Text] [PDF]
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 M. Ohkita, M. Sugii, Y. Ka, A. Kitamura, T. Mori, T. Hayashi, M. Takaoka, and Y. Matsumura Differential Effects of Different Statins on Endothelin-1 Gene Expression and Endothelial NOS Phosphorylation in Porcine Aortic Endothelial Cells. Experimental Biology and Medicine, June 1, 2006; 231(6): 772 - 776. [Abstract] [Full Text] [PDF]
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J. J. Maguire, K. E. Wiley, R. E. Kuc, V. E. A. Stoneman, M. R. Bennett, and A. P. Davenport Endothelin-Mediated Vasoconstriction in Early Atherosclerosis Is Markedly Increased in ApoE-/- Mouse but Prevented by Atorvastatin. Experimental Biology and Medicine, June 1, 2006; 231(6): 806 - 812. [Abstract] [Full Text] [PDF]
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H. Bujo and Y. Saito Modulation of Smooth Muscle Cell Migration by Members of the Low-Density Lipoprotein Receptor Family Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1246 - 1252. [Abstract] [Full Text] [PDF]
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 M. Arora, L. Chen, M. Paglia, I. Gallagher, J. E. Allen, Y. M. Vyas, A. Ray, and P. Ray Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells PNAS, May 16, 2006; 103(20): 7777 - 7782. [Abstract] [Full Text] [PDF]
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V. Liebe, M. Brueckmann, M. Borggrefe, and J. J. Kaden Statin therapy of calcific aortic stenosis: hype or hope? Eur. Heart J., April 1, 2006; 27(7): 773 - 778. [Abstract] [Full Text] [PDF]
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 J. Segura, J. A. Garcia-Donaire, M. Praga, and L. M. Ruilope Chronic Kidney Disease as a Situation of High Added Risk in Hypertensive Patients J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S136 - S140. [Abstract] [Full Text] [PDF]
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G. D'Amico Statins and Renal Diseases: From Primary Prevention to Renal Replacement Therapy. J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S148 - S152. [Abstract] [Full Text] [PDF]
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S. Shibata, M. Nagase, and T. Fujita Fluvastatin Ameliorates Podocyte Injury in Proteinuric Rats via Modulation of Excessive Rho Signaling J. Am. Soc. Nephrol., March 1, 2006; 17(3): 754 - 764. [Abstract] [Full Text] [PDF]
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G. Loirand, P. Guerin, and P. Pacaud Rho Kinases in Cardiovascular Physiology and Pathophysiology Circ. Res., February 17, 2006; 98(3): 322 - 334. [Abstract] [Full Text] [PDF]
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R. Paumelle, C. Blanquart, O. Briand, O. Barbier, C. Duhem, G. Woerly, F. Percevault, J.-C. Fruchart, D. Dombrowicz, C. Glineur, et al. Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator-Activated Receptor-{alpha} via Inhibition of the Protein Kinase C Signaling Pathway Circ. Res., February 17, 2006; 98(3): 361 - 369. [Abstract] [Full Text] [PDF]
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M. J. Haas, M. H. Horani, S. A. Parseghian, and A. D. Mooradian Statins Prevent Dextrose-Induced Endothelial Barrier Dysfunction, Possibly Through Inhibition of Superoxide Formation Diabetes, February 1, 2006; 55(2): 474 - 479. [Abstract] [Full Text] [PDF]
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P. Amarenco and M. A. Moskowitz The Dynamics of Statins: From Event Prevention to Neuroprotection Stroke, February 1, 2006; 37(2): 294 - 296. [Full Text] [PDF]
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A. D. Mooradian, M. J. Haas, O. Batejko, M. Hovsepyan, and S. S. Feman Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats Diabetes, October 1, 2005; 54(10): 2977 - 2982. [Abstract] [Full Text] [PDF]
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H. Shimokawa and A. Takeshita Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1767 - 1775. [Abstract] [Full Text] [PDF]
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A. Jula, J. Marniemi, T. Ronnemaa, A. Virtanen, and R. Huupponen Effects of Diet and Simvastatin on Fatty Acid Composition in Hypercholesterolemic Men: A Randomized Controlled Trial Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1952 - 1959. [Abstract] [Full Text] [PDF]
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M.-Y. Tseng, M. Czosnyka, H. Richards, J. D. Pickard, and P. J. Kirkpatrick Effects of Acute Treatment With Pravastatin on Cerebral Vasospasm, Autoregulation, and Delayed Ischemic Deficits After Aneurysmal Subarachnoid Hemorrhage: A Phase II Randomized Placebo-Controlled Trial Stroke, August 1, 2005; 36(8): 1627 - 1632. [Abstract] [Full Text] [PDF]
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R. Corti, V. Fuster, Z. A. Fayad, S. G. Worthley, G. Helft, W. F. Chaplin, J. Muntwyler, J. F. Viles-Gonzalez, J. Weinberger, D. A. Smith, et al. Effects of Aggressive Versus Conventional Lipid-Lowering Therapy by Simvastatin on Human Atherosclerotic Lesions: A Prospective, Randomized, Double-Blind Trial With High-Resolution Magnetic Resonance Imaging J. Am. Coll. Cardiol., July 5, 2005; 46(1): 106 - 112. [Abstract] [Full Text] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Nabauer, and M. Weis Statins Decrease Toll-Like Receptor 4 Expression and Downstream Signaling in Human CD14+ Monocytes Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1439 - 1445. [Abstract] [Full Text] [PDF]
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C. A. Argmann, J. Y. Edwards, C. G. Sawyez, C. H. O'Neil, R. A. Hegele, J. G. Pickering, and M. W. Huff Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition: A ROLE FOR RhoA IN ABCA1-MEDIATED CHOLESTEROL EFFLUX J. Biol. Chem., June 10, 2005; 280(23): 22212 - 22221. [Abstract] [Full Text] [PDF]
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M. Yamakuchi, J. J.M. Greer, S. J. Cameron, K. Matsushita, C. N. Morrell, K. Talbot-Fox, W. M. Baldwin III, D. J. Lefer, and C. J. Lowenstein HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size Circ. Res., June 10, 2005; 96(11): 1185 - 1192. [Abstract] [Full Text] [PDF]
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H. Lorenz, C. Junger, K. Seidl, A. Gitt, S. Schneider, R. Schiele, H. Wienbergen, R. Winkler, M. Gottwik, W. Delius, et al. Do statins influence the prognostic impact of non-sustained ventricular tachycardia after ST-elevation myocardial infarction? Eur. Heart J., June 1, 2005; 26(11): 1078 - 1085. [Abstract] [Full Text] [PDF]
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R. Sugano, H. Matsuoka, N. Haramaki, H. Umei, E. Murase, K. Fukami, S. Iida, H. Ikeda, and T. Imaizumi Polymorphonuclear Leukocytes May Impair Endothelial Function: Results of Crossover Randomized Study of Lipid-Lowering Therapies Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1262 - 1267. [Abstract] [Full Text] [PDF]
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L. H. Smith, M. S. Petrie, J. D. Morrow, J. A. Oates, and D. E. Vaughan The sterol response element binding protein regulates cyclooxygenase-2 gene expression in endothelial cells J. Lipid Res., May 1, 2005; 46(5): 862 - 871. [Abstract] [Full Text] [PDF]
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Y. Urano, I. Hayashi, N. Isoo, P. C. Reid, Y. Shibasaki, N. Noguchi, T. Tomita, T. Iwatsubo, T. Hamakubo, and T. Kodama Association of active {gamma}-secretase complex with lipid rafts J. Lipid Res., May 1, 2005; 46(5): 904 - 912. [Abstract] [Full Text] [PDF]
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A. G. Olsson, G. G. Schwartz, M. Szarek, W. J. Sasiela, M. D. Ezekowitz, P. Ganz, M. F. Oliver, D. Waters, and A. Zeiher High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial Eur. Heart J., May 1, 2005; 26(9): 890 - 896. [Abstract] [Full Text] [PDF]
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S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF]
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A. Schafer, D. Fraccarollo, M. Eigenthaler, P. Tas, A. Firnschild, S. Frantz, G. Ertl, and J. Bauersachs Rosuvastatin Reduces Platelet Activation in Heart Failure: Role of NO Bioavailability Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 1071 - 1077. [Abstract] [Full Text] [PDF]
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R. Madonna, P. Di Napoli, M. Massaro, A. Grilli, M. Felaco, A. De Caterina, D. Tang, R. De Caterina, and Y.-J. Geng Simvastatin Attenuates Expression of Cytokine-inducible Nitric-oxide Synthase in Embryonic Cardiac Myoblasts J. Biol. Chem., April 8, 2005; 280(14): 13503 - 13511. [Abstract] [Full Text] [PDF]
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L. Sironi, E. Gianazza, P. Gelosa, U. Guerrini, E. Nobili, A. Gianella, B. Cremonesi, R. Paoletti, and E. Tremoli Rosuvastatin, but not Simvastatin, Provides End-Organ Protection in Stroke-Prone Rats by Antiinflammatory Effects Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 598 - 603. [Abstract] [Full Text] [PDF]
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M. Fu, J. Zhang, Y.-H. Tseng, T. Cui, X. Zhu, Y. Xiao, Y. Mou, H. De Leon, M. M.J. Chang, Y. Hamamori, et al. Rad GTPase Attenuates Vascular Lesion Formation by Inhibition of Vascular Smooth Muscle Cell Migration Circulation, March 1, 2005; 111(8): 1071 - 1077. [Abstract] [Full Text] [PDF]
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T. Senokuchi, T. Matsumura, M. Sakai, M. Yano, T. Taguchi, T. Matsuo, K. Sonoda, D. Kukidome, K. Imoto, T. Nishikawa, et al. Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway J. Biol. Chem., February 25, 2005; 280(8): 6627 - 6633. [Abstract] [Full Text] [PDF]
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A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Statins and Blood Coagulation Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 287 - 294. [Abstract] [Full Text] [PDF]
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Y. Birnbaum, Y. Ye, S. Rosanio, S. Tavackoli, Z.-Y. Hu, E. R. Schwarz, and B. F. Uretsky Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury Cardiovasc Res, February 1, 2005; 65(2): 345 - 355. [Abstract] [Full Text] [PDF]
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