Statins as Potent Antiinflammatory Drugs
2002; Lippincott Williams & Wilkins; Volume: 106; Issue: 16 Linguagem: Inglês
10.1161/01.cir.0000033635.42612.88
ISSN1524-4539
Autores Tópico(s)Inflammatory mediators and NSAID effects
ResumoHomeCirculationVol. 106, No. 16Statins as Potent Antiinflammatory Drugs Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBStatins as Potent Antiinflammatory Drugs David J. Lefer, PhD David J. LeferDavid J. Lefer From the Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, La. Originally published15 Oct 2002https://doi.org/10.1161/01.CIR.0000033635.42612.88Circulation. 2002;106:2041–2042Statin drugs have previously been shown to very significantly reduce cardiovascular disease events in a number of large clinical trials.1 As a result, statins are now considered to represent one of the most powerful classes of agents for the treatment of cardiovascular diseases.2 Statins are rapidly becoming frontline therapy for diabetes mellitus, hypertension, and other known cardiovascular disease risk factors. Originally, reductions in cardiovascular disease events and mortality and overall improved outcomes were attributed to dramatic reductions in circulating serum lipid levels that were mediated by inhibition of liver 3-hydroxy 3-methyl glutaryl coenzyme A (HMG-CoA) reductase.1 However, more recent experimental and clinical investigations have revealed that statins can exert a number of cholesterol-independent, cardioprotective actions. In this regard, statins are potent modulators of endothelial cell nitric oxide synthase (eNOS) function and have been shown to upregulate eNOS enzyme levels and nitric oxide (NO) synthesis.3–5See p 2104Pruefer and colleagues6 now demonstrate in this issue of Circulation powerful antiinflammatory properties of simvastatin in the setting of Staphylococcus aureus α-toxin infection. Endotoxemia represents a potent stimulus for vascular inflammation that is characterized by enhanced leukocyte recruitment to the microvascular endothelium. The report by Pruefer et al6 elegantly demonstrates that pretreatment with clinically relevant doses of simvastatin attenuates endotoxin-induced leukocyte rolling and transmigration in the rat mesentery. Simvastatin was administered 18 hours before administration of endotoxin. Simvastatin therapy also resulted in a 50% upregulation of eNOS expression in the endothelium and a 50% decrease in endothelial cell P-selectin expression. Circulating cholesterol levels were not reported in this study, but it is unlikely that acute statin therapy would alter lipid levels in rodents. The data presented in this paper are very convincing and provide yet another example of the potent antiinflammatory actions of acute statin therapy. The results of the study by Pruefer et al6 may have important clinical implications for the treatment of inflammatory disease states with statin therapy.Previous experimental and clinical studies have also demonstrated that statins can downregulate both acute and chronic inflammatory processes. Early evidence for the direct vascular effects of statins was provided by clinical studies demonstrating improvements in coronary endothelial function in patients as early as 1 month after the initiation of statin therapy.7,8 It soon became evident that statins had potent actions on the vascular endothelium that might be mediated by eNOS. Landmark studies by Laufs et al3–5 reported that statins upregulate eNOS function under baseline conditions and after hypoxic conditions. Laufs and colleagues3 reported that simvastatin and lovastatin increased endothelial cell eNOS mRNA half-life from 13 to 38 hours. Furthermore, Laufs and colleagues3–5 discovered that statins augmented endothelial NOS function via inhibition of biosynthesis of L-mevalonate and the isoprenoid geranylgeranylpyrophosphate (GGPP). GGPP is involved in the posttranslational modification of a variety of proteins, including eNOS, and Ras-like proteins, such as Rho. Inhibition of Rho results in a 3-fold increase in eNOS and nitrite generation, since Rho is an endogenous inhibitor of endothelial NO generation. More recently, Kureishi et al9 have provided a very elegant demonstration that simvastatin activates the protein kinase Akt resulting in enhanced eNOS phosphorylation and NO generation via eNOS. The results of Kureishi and colleagues9 demonstrate that statins can produce a very rapid improvement in endothelial function that is independent of changes in eNOS mRNA levels. Kureishi et al9 also reported for the first time that simvastatin treatment can attenuate endothelial cell apoptosis and augment angiogenesis in the ischemic rabbit hind limb model system. Since eNOS-derived NO represents a highly potent antiinflammatory signaling pathway, the investigation of statins a antiinflammatory agents is very logical.After the landmark discovery that statins upregulate eNOS function, a number of studies have reported very powerful antiinflammatory actions of statins that are largely eNOS-dependent. Lefer et al10 were among the first to report antiinflammatory actions of statins in an in vitro model of acute myocardial ischemia-reperfusion. Subsequently, Pruefer et al11 utilized intravital microscopy to demonstrate that statin therapy very significantly inhibits leukocyte–endothelial cell interactions independently of any lipid lowering actions in normocholesterolemic rats. More recently, rosuvastatin has been shown to exhibit similar antiinflammatory properties in the microvasculature.12 Since these initial studies of statin therapy in acute myocardial infarction in vitro, there have been a number of in vivo reports demonstrating highly potent antiinflammatory and cardioprotective actions of statins in the setting of acute myocardial infarction in normocholesterolemic,13 hypercholesterolemic,13 and diabetic14 animal models. The cardioprotective actions of statin therapy are not transient in nature and have been shown to be present at 6 months of reperfusion after statin therapy before the onset of acute myocardial infarction.15 Statin therapy has been shown to inhibit leukocyte accumulation in the ischemic-reperfused myocardium and to be highly dependent on eNOS, since eNOS deficient mice are completely resistant to statin-mediated cardioprotection.Clinical evidence supporting the potent antiinflammatory and cardioprotective actions is beginning to emerge. It is now well appreciated that atherogenesis is primarily an inflammatory process mediated in large part by the recruitment of blood monocytes to the vessel wall.16 Statin therapy has been shown to attenuate vascular inflammation in patients, as evidenced by significant reductions in inflammatory markers such as high sensitivity C-reactive protein (hsCRP)17 and soluble CD40 ligand.18 Furthermore, it has been reported very recently that statin therapy in patients is associated with a significant reduction in mortality very early after percutaneous coronary interventions.19 It is possible that these acute effects of statin therapy may be related to attenuation of inflammatory processes. In addition, results from the Platelet Receptor Inhibition in ischemic Syndrome Management (PRISM) study20 clearly demonstrated that withdrawal of statin therapy very significantly increases event rates in patients with acute coronary syndromes. Interestingly, the increased event rate occurred during the first week after the onset of symptoms and was independent of cholesterol levels.In summary, statins are now becoming recognized as powerful antiinflammatory agents that exert beneficial effects beyond low-density lipoprotein cholesterol reduction. Upregulation of endothelial function (ie, eNOS enzyme activity) is thought to be a primary mechanism responsible for these antiinflammatory properties. Pruefer et al6 now provide additional evidence that statin therapy attenuates inflammation and further extend out understanding of this very exciting class of cardiovascular agents.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Dr Lefer is a speaker for Merck and Company and has received research grants from Merck and Company and AstraZeneca.FootnotesCorrespondence to David J. Lefer, PhD, Department of Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA 71130. E-mail [email protected] References 1 Scandinavian Simvastatin Survival Study (4S) Group. Randomized trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study. Lancet. 1994; 344: 1383–1389.MedlineGoogle Scholar2 Lefer AM, Scalia R, Lefer DJ. Vascular effects of HMG-CoA reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease. Cardiovasc Res. 2001; 49: 281–287.CrossrefMedlineGoogle Scholar3 Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97: 1129–1135.CrossrefMedlineGoogle Scholar4 Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA activity stability by Rho GTPase. J Biol Chem. 1998; 273: 24266–24271.CrossrefMedlineGoogle Scholar5 Laufs U, La Fata V, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem. 1997; 272: 31725–31729.CrossrefMedlineGoogle Scholar6 Pruefer D, Makowski J, Schnell M, et al. Simvastatin inhibits inflammatory properties of staphylococcus aureus α-toxin. Circulation. 2002; 106: 2104–2110.LinkGoogle Scholar7 Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995; 332: 481–487.CrossrefMedlineGoogle Scholar8 O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997; 95: 1126–1131.CrossrefMedlineGoogle Scholar9 Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000; 6: 1004–1010.CrossrefMedlineGoogle Scholar10 Lefer AM, Campbell B, Shin YK, et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation. 1999; 100: 178–184.CrossrefMedlineGoogle Scholar11 Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol. 1999; 19: 2894–2900.CrossrefMedlineGoogle Scholar12 Stalker TJ, Lefer AM, Scalia R. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on microvascular endothelium, the role of mevalonic acid. Br J Pharmacol. 2001; 133: 406–412.CrossrefMedlineGoogle Scholar13 Scalia R, Gooszen ME, Jones SP, et al. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation. 2001; 103: 2598–2603.CrossrefMedlineGoogle Scholar14 Lefer DJ, Scalia R, Jones SP, et al. HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury.FASEB J. April 27, 2001. 10.1096-/fj00–0819fje. Available at http://www.fasebj.org. Accessed September 18, 2002.Google Scholar15 Jones SP, Trocha SD, Lefer DJ. Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion. Arterioscler Thromb Vasc Biol. 2001; 21: 2059–2064.CrossrefMedlineGoogle Scholar16 Ridker PM, Rifai N, Pfeffer M, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999; 100: 230–235.CrossrefMedlineGoogle Scholar17 Cipollone F, Mezzetti A, Porreca E, et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation. 2002; 106: 399–402.LinkGoogle Scholar18 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.CrossrefMedlineGoogle Scholar19 Chan AW, Bhatt DL, Chew DP, et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation. 2002; 105: 691–696.CrossrefMedlineGoogle Scholar20 Heeschen C, Hamm CW, Laufs U, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002; 105: 1446–1452.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Markova A, Deterding K, Port K, Bantel H, Manns M, Cornberg M and Wedemeyer H (2020) Liver stiffness across different chronic liver disease under therapy with statin in a real life cohort, European Journal of Gastroenterology & Hepatology, 10.1097/MEG.0000000000001719, 32:2, (223-229), Online publication date: 1-Feb-2021. Takahashi S, Kasama S, Toyama T, Suzuki S, Ito Y, Nakata T, Kasahara M and Kurabayashi M (2019) Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity after reperfusion therapy in patients with first ST-segment elevation myocardial infarction and normal low-density lipoprotein cholesterol, Journal of Nuclear Cardiology, 10.1007/s12350-019-01857-y, 28:4, (1449-1457), Online publication date: 1-Aug-2021. Sun C, Zheng W, Liang L, Liu Z, Sun W, Tang R and De Luca L (2021) Ezetimibe Improves Rosuvastatin Effects on Inflammation and Vascular Endothelial Function in Acute Coronary Syndrome Patients Undergoing PCI, Journal of Interventional Cardiology, 10.1155/2021/2995602, 2021, (1-7), Online publication date: 7-Sep-2021. Zhao C, Zuckerman S, Cai C, Kilari S, Singh A, Simeon M, von Recum H, Korley J and Misra S (2020) Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula, Journal of the American Heart Association, 9:24, Online publication date: 15-Dec-2020. Hashemi Madani N, Ismail-Beigi F, Poustchi H, Nalini M, Sepanlou S, Malek M, Abbasi M, Khajavi A, Khamseh M and Malekzadeh R (2020) Impaired fasting glucose and major adverse cardiovascular events by hypertension and dyslipidemia status: the Golestan cohort study, BMC Cardiovascular Disorders, 10.1186/s12872-020-01390-8, 20:1, Online publication date: 1-Dec-2020. Minz M, Bansal M and Kasliwal R (2020) Statins and SARS-CoV-2 disease: Current concepts and possible benefits, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 10.1016/j.dsx.2020.10.021, 14:6, (2063-2067), Online publication date: 1-Nov-2020. Scridon A and Martínez-Rubio A (2020) Antiarrhythmic Properties of Non-Antiarrhythmic Drugs in Atrial Fibrillation: Upstream Therapy Antiarrhythmic Drugs, 10.1007/978-3-030-34893-9_7, (307-377), . Penkauskas T, Zentelyte A, Ganpule S, Valincius G and Preta G (2020) Pleiotropic effects of statins via interaction with the lipid bilayer: A combined approach, Biochimica et Biophysica Acta (BBA) - Biomembranes, 10.1016/j.bbamem.2020.183306, 1862:9, (183306), Online publication date: 1-Sep-2020. Kimer N, Grønbæk H, Fred R, Hansen T, Deshmukh A, Mann M and Bendtsen F (2020) Atorvastatin for prevention of disease progression and hospitalisation in liver cirrhosis: protocol for a randomised, double-blind, placebo-controlled trial, BMJ Open, 10.1136/bmjopen-2019-035284, 10:1, (e035284), Online publication date: 1-Jan-2020. Kunal S, Gupta K and Gupta S (2020) Statins in COVID-19: A new ray of hope, Heart & Lung, 10.1016/j.hrtlng.2020.07.012, 49:6, (887-889), Online publication date: 1-Nov-2020. Markova A and Wedemeyer H (2020) Statine bei Lebererkrankungen: gut oder schlecht?, Gastro-News, 10.1007/s15036-020-0278-0, 7:2, (44-47), Online publication date: 1-Apr-2020. Nerlekar N, Thakur U, Lin A, Koh J, Potter E, Liu D, Muthalaly R, Rashid H, Cameron J, Dey D and Wong D (2020) The Natural history of Epicardial Adipose Tissue Volume and Attenuation: A long-term prospective cohort follow-up study, Scientific Reports, 10.1038/s41598-020-63135-z, 10:1, Online publication date: 1-Dec-2020. Chaudhary R, Kinderytė M, Chaudhary R, Sukhi A, Bliden K, Tantry U and Gurbel P (2019) HDL3-C is a Marker of Coronary Artery Disease Severity and Inflammation in Patients on Statin Therapy, Cardiovascular Revascularization Medicine, 10.1016/j.carrev.2018.12.019, 20:11, (1001-1006), Online publication date: 1-Nov-2019. Gupta M, Sharma R and Kumar A (2019) Comparative potential of Simvastatin, Rosuvastatin and Fluvastatin against bacterial infection: an in silico and in vitro study, Oriental Pharmacy and Experimental Medicine, 10.1007/s13596-019-00359-z, 19:3, (259-275), Online publication date: 1-Sep-2019. Kasama S, Toyama T, Suzuki S, Ito Y, Matsumoto N, Kurabayashi M and Kasahara M (2019) Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity and cardiac events in patients with ischemic cardiomyopathy and mild to moderate heart failure, Nuclear Medicine Communications, 10.1097/MNM.0000000000000955, 40:2, (159-168), Online publication date: 1-Feb-2019. Jonnalagadda V and Char H (2018) Effect of resveratrol in type 2 diabetes oxidative stress markers: a reassessment, Acta Diabetologica, 10.1007/s00592-018-1155-6, 55:7, (757-757), Online publication date: 1-Jul-2018. de Lima-Seolin B, Hennemann M, Fernandes R, Colombo R, Bonetto J, Teixeira R, Khaper N, Godoy A, Litvin I, Sander da Rosa Araujo A, Schenkel P and Belló-Klein A (2018) Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2018.01.127, 99, (704-714), Online publication date: 1-Mar-2018. Gupta M and Kumar A Comparison of Minimum Inhibitory Concentration (MIC) value of statin drugs: A Systematic Review, Anti-Infective Agents, 10.2174/2211352516666180629124433, 17:1, (4-19) Govorkova M, Milman T, Ying G, Pan W and Silkiss R (2018) Inflammatory Mediators in Xanthelasma Palpebrarum: Histopathologic and Immunohistochemical Study, Ophthalmic Plastic & Reconstructive Surgery, 10.1097/IOP.0000000000000921, 34:3, (225-230), Online publication date: 1-May-2018. Majeed M, Anil C, Amaravathi A and Kondaveti S (2017) COMPARATIVE STUDY OF ANTI-INFLAMMATORY ACTIVITY OF ROSUVASTATIN WITH THAT OF ASPIRIN IN ALBINO RATS, Journal of Evidence Based Medicine and Healthcare, 10.18410/jebmh/2017/870, 4:74, (4368-4371), Online publication date: 12-Sep-2017. Akarsu M, Saygun O, Aydinuraz K, Aydin O, Daphan C, Tanrıkulu F, Kisa U and Comu F (2016) The Effects of Simvastatin on Ischemia Reperfusion Injury in an Experimental Colon Anastomosis Model, Indian Journal of Surgery, 10.1007/s12262-016-1493-y, 79:5, (390-395), Online publication date: 1-Oct-2017. Keser T, Vučković F, Barrios C, Zierer J, Wahl A, Akinkuolie A, Štambuk J, Nakić N, Pavić T, Periša J, Mora S, Gieger C, Menni C, Spector T, Gornik O and Lauc G (2017) Effects of statins on the immunoglobulin G glycome, Biochimica et Biophysica Acta (BBA) - General Subjects, 10.1016/j.bbagen.2017.02.029, 1861:5, (1152-1158), Online publication date: 1-May-2017. Kucukseymen S (2017) Inflammation Effects on Stent Restenosis, Angiology, 10.1177/0003319717701659, 68:8, (741-741), Online publication date: 1-Sep-2017. Kim R, Loomba R, Prokop L and Singh S (2017) Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis, Clinical Gastroenterology and Hepatology, 10.1016/j.cgh.2017.04.039, 15:10, (1521-1530.e8), Online publication date: 1-Oct-2017. Ghanim H, Green K, Abuaysheh S, Patel R, Batra M, Chaudhuri A, Makdissi A, Kuhadiya N and Dandona P (2017) Ezetimibe and simvastatin combination inhibits and reverses the pro-inflammatory and pro-atherogenic effects of cream in obese patients, Atherosclerosis, 10.1016/j.atherosclerosis.2017.06.010, 263, (278-286), Online publication date: 1-Aug-2017. Patil M, Patil R, Mohammad S and Maheshwari V (2017) Bioactivities of phenolics-rich fraction from Diaporthe arengae TATW2, an endophytic fungus from Terminalia arjuna (Roxb.), Biocatalysis and Agricultural Biotechnology, 10.1016/j.bcab.2017.05.002, 10, (396-402), Online publication date: 1-Apr-2017. Katsi V, Georgiopoulos G, Laina A, Koutli E, Parissis J, Tsioufis C, Nihoyannopoulos P and Tousoulis D (2017) Left ventricular ejection fraction as therapeutic target: is it the ideal marker?, Heart Failure Reviews, 10.1007/s10741-017-9624-5, 22:6, (641-655), Online publication date: 1-Nov-2017. Kuai R, Li D, Chen Y, Moon J and Schwendeman A (2016) High-Density Lipoproteins: Nature's Multifunctional Nanoparticles, ACS Nano, 10.1021/acsnano.5b07522, 10:3, (3015-3041), Online publication date: 22-Mar-2016. Simões F, de Batista P, Botelho T, Ribeiro-Júnior R, Padilha A and Vassallo D (2016) Treatment with high dose of atorvastatin reduces vascular injury in diabetic rats, Pharmacological Reports, 10.1016/j.pharep.2016.04.022, 68:5, (865-873), Online publication date: 1-Oct-2016. Soko N, Masimirembwa C and Dandara C (2016) Pharmacogenomics of Rosuvastatin: A Glocal (Global+Local) African Perspective and Expert Review on a Statin Drug, OMICS: A Journal of Integrative Biology, 10.1089/omi.2016.0114, 20:9, (498-509), Online publication date: 1-Sep-2016. Cabrera L and Abraldes J (2016) Statins: the Panacea of Cirrhosis?, Current Hepatology Reports, 10.1007/s11901-016-0287-9, 15:1, (1-7), Online publication date: 1-Mar-2016. Thangamani S, Mohammad H, Abushahba M, Hamed M, Sobreira T, Hedrick V, Paul L and Seleem M (2015) Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent, Scientific Reports, 10.1038/srep16407, 5:1, Online publication date: 1-Dec-2015. Wang Y, Bai L, Lin Y, Chen Y, Guan H, Zhu N, Li Y, Gao S, Sun L, Zhao S, Fan J and Liu E (2015) Combined use of probucol and cilostazol with atorvastatin attenuates atherosclerosis in moderately hypercholesterolemic rabbits, Lipids in Health and Disease, 10.1186/s12944-015-0083-5, 14:1, Online publication date: 1-Dec-2015. Hsu C, Lin C, Hsiao L and Yang C (2015) Mevastatin ameliorates sphingosine 1-phosphate-induced COX-2/PGE2-dependent cell migration via FoxO1 and CREB phosphorylation and translocation, British Journal of Pharmacology, 10.1111/bph.13326, 172:22, (5360-5376), Online publication date: 1-Nov-2015. Variya B, Patel S, Trivedi J, Gandhi H and Rathod S (2015) Comparative evaluation of HMG CoA reductase inhibitors in experimentally-induced myocardial necrosis: Biochemical, morphological and histological studies, European Journal of Pharmacology, 10.1016/j.ejphar.2015.07.024, 764, (283-291), Online publication date: 1-Oct-2015. Arévalo-Lorido J, Carretero-Gómez J, Fernández-Recio J, Alvarez-Oliva A, Gutiérrez-Montaño C, Najarro-Díez F and Martín-Sánchez M (2015) Lowering C-reactive protein with statins after an ischemic stroke avoids mortality and readmissions. A prospective cohort study, Annals of Medicine, 10.3109/07853890.2015.1010227, 47:3, (226-232), Online publication date: 3-Apr-2015. Skarping I, Brand J, Hall P and Borgquist S (2015) Effects of statin use on volumetric mammographic density: results from the KARMA study, BMC Cancer, 10.1186/s12885-015-1457-9, 15:1, Online publication date: 1-Dec-2015. Sano H, Kasama S, Fujimoto S, Toyama T, Takama N, Koitabashi N, Ichikawa S, Suzuki Y, Matsumoto N, Sato Y and Kurabayashi M (2014) Effects of Statin Therapy on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients With Chronic Heart Failure, Medicine, 10.1097/MD.0000000000000214, 93:27, (e214), Online publication date: 1-Dec-2014. Gadkar K, Budha N, Baruch A, Davis J, Fielder P and Ramanujan S (2014) A Mechanistic Systems Pharmacology Model for Prediction of LDL Cholesterol Lowering by PCSK9 Antagonism in Human Dyslipidemic Populations, CPT: Pharmacometrics & Systems Pharmacology, 10.1038/psp.2014.47, 3:11, (1-9), Online publication date: 1-Nov-2014. La Mura V, Pasarín M, Rodriguez-Vilarrupla A, García-Pagán J, Bosch J and Abraldes J (2014) Liver sinusoidal endothelial dysfunction after LPS administration: A role for inducible-nitric oxide synthase, Journal of Hepatology, 10.1016/j.jhep.2014.07.014, 61:6, (1321-1327), Online publication date: 1-Dec-2014. Wani M, Goswami T, Chaudhary D, Singh R and Dhama K (2014) Mitigation of Septic Signs by Pravastatin during LPS Co-Administered Hen-Egg White Lysozyme Immunization in Mice, International Journal of Pharmacology, 10.3923/ijp.2014.389.397, 10:7, (389-397), Online publication date: 15-Sep-2014. Lim S (2013) Role of Statins in Coronary Artery Disease, Chonnam Medical Journal, 10.4068/cmj.2013.49.1.1, 49:1, (1), . La Mura V, Pasarín M, Meireles C, Miquel R, Rodríguez-Vilarrupla A, Hide D, Gracia-Sancho J, García-Pagán J, Bosch J and Abraldes J (2013) Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction, Hepatology, 10.1002/hep.26127, 57:3, (1172-1181), Online publication date: 1-Mar-2013. Brewer T, Masuda H, Liu D, Shen Y, Liu P, Iwamoto T, Kai K, Barnett C, Woodward W, Reuben J, Yang P, Hortobagyi G and Ueno N (2013) Statin use in primary inflammatory breast cancer: a cohort study, British Journal of Cancer, 10.1038/bjc.2013.342, 109:2, (318-324), Online publication date: 1-Jul-2013. Wani M, Goswami T, Mir R, Chaudhuri P and Dhama K (2013) Moderation of Immunopathological Parameters by Pravastatin in Pasteurella multocida (Pm52) Induced Septicaemic Mice, International Journal of Pharmacology, 10.3923/ijp.2013.513.523, 9:8, (513-523), Online publication date: 1-Nov-2013. Adam S and Hoppe C (2012) Potential role for statins in sickle cell disease, Pediatric Blood & Cancer, 10.1002/pbc.24443, 60:4, (550-557), Online publication date: 1-Apr-2013. Alele J, Luttrell L, Hollis B, Luttrell D and Hunt K (2013) Relationship between vitamin D status and incidence of vascular events in the Veterans Affairs Diabetes Trial, Atherosclerosis, 10.1016/j.atherosclerosis.2013.03.024, 228:2, (502-507), Online publication date: 1-Jun-2013. Tsai N, Lee L, Huang C, Chang W, Chen S, Wang H, Lin Y, Lin W, Chiang Y, Lin T, Cheng B, Su Y, Kung C, Hung S, Chang H and Lu C (2012) The association of statin therapy and high-sensitivity C‐reactive protein level for predicting clinical outcome in acute non-cardioembolic ischemic stroke, Clinica Chimica Acta, 10.1016/j.cca.2012.07.021, 413:23-24, (1861-1865), Online publication date: 1-Nov-2012. Schumacher H, Habre W, Friedrich C, Sieck M, Chen L, Clayburne G and Von Feldt J (2014) Synovial xanthomatosis: are there clues to mechanisms for this rare disease?, Modern Rheumatology, 10.3109/s10165-012-0592-2, 22:6, (907-911), Online publication date: 1-Nov-2012. Nakayama K, Tanabe Y, Obara K and Ishikawa T (2012) Mechanosensitivity of Pancreatic β-cells, Adipocytes, and Skeletal Muscle Cells: The Therapeutic Targets of Metabolic Syndrome Mechanically Gated Channels and their Regulation, 10.1007/978-94-007-5073-9_14, (379-404), . Purnak T and Purnak S (2012) The inflammatory markers in psoriasis, British Journal of Dermatology, 10.1111/j.1365-2133.2012.10970.x, 167:2, (457-458), Online publication date: 1-Aug-2012. Zhang L, Zhang S, Jiang H, Sun A, Zou Y and Ge J (2010) Effects of Statin Treatment on Cardiac Function in Patients With Chronic Heart Failure: A Meta-Analysis of Randomized Controlled Trials, Clinical Cardiology, 10.1002/clc.20821, 34:2, (117-123), Online publication date: 1-Feb-2011. Dentali F, Gianni M, Squizzato A, Ageno W, Castiglioni L, Maroni L, Hylek E, Grandi A, Cazzani E, Venco A and Guasti L (2017) Use of statins and recurrence of atrial fibrillation after catheter ablation or electrical cardioversion, Thrombosis and Haemostasis, 10.1160/TH10-10-0660, 106:08, (363-370), . Turpie A and Esmon C (2017) Venous and arterial thrombosis – pathogenesis and the rationale for anticoagulation, Thrombosis and Haemostasis, 10.1160/TH10-10-0683, 105:04, (586-596), . Niccoli G, Cosentino N, Spaziani C, Minelli S, Fracassi F and Crea F (2014) New strategies for the management of no-reflow after primary percutaneous coronary intervention, Expert Review of Cardiovascular Therapy, 10.1586/erc.11.49, 9:5, (615-630), Online publication date: 1-May-2011. Lyons K, McVeigh G and Harbinson M (2010) Statins in Heart Failure—Where Do We Stand?, Cardiovascular Drugs and Therapy, 10.1007/s10557-010-6269-1, 25:1, (99-104), Online publication date: 1-Feb-2011. NEGI S, SHUKRULLAH I, VELEDAR E, BLOOM H, JONES D and DUDLEY S (2010) Statin Therapy for the Prevention of Atrial Fibrillation Trial (SToP AF trial), Journal of Cardiovascular Electrophysiology, 10.1111/j.1540-8167.2010.01925.x, 22:4, (414-419), Online publication date: 1-Apr-2011. Blomkalns A, Stoll L, Shaheen W, Romig-Martin S, Dickson E, Weintraub N and Denning G (2011) Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells, Journal of Inflammation, 10.1186/1476-9255-8-4, 8:1, (4), . KUO C (2010) Statins, Inflammation, Oxidative Stress, and Atrial Fibrillation, Journal of Cardiovascular Electrophysiology, 10.1111/j.1540-8167.2010.01946.x, 22:4, (420-421), Online publication date: 1-Apr-2011. Kevil C, Kolluru G, Pattillo C and Giordano T (2011) Inorganic nitrite therapy: historical perspective and future directions, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2011.04.042, 51:3, (576-593), Online publication date: 1-Aug-2011. Abraldes J, La Mura V and Bosch J (2010) Statins in Portal Hypertension Portal Hypertension V, 10.1002/9781444393989.ch19
Referência(s)