Cited by 343Nitric Oxide and Endothelin EffectsLipoproteins and Cardiovascular HealthCardiovascular Health and Disease Prevention

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Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions

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Kaesemeyer, Wayne H., Caldwell, Ruth B., Huang, Jianzhong, Caldwell, R.William·1999·Journal of the American College of Cardiology

DOI 10.1016/s0735-1097(98)00514-2

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Abstract

Objectives We tested the hypothesis that pravastatin (PRA) activates endothelial nitric oxide synthase (eNOS).Background Pravastatin has been found to have clinical benefits beyond those predicted by its actions in reducing plasma low density lipoprotein cholesterol (LDL). Both PRA and simvastatin (SIM) are equally effective in reducing LDL, but only PRA reduces platelet aggregation and is an effective vasodilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodilates.Methods We determined PRA and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cells. Nitric oxide was measured by using a NO electrode and by an assay for conversion of hemoglobin to methemoglobin. Specificity of NOS activation was tested by using the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 1 mmol/liter) in the presence or absence of excess L-arginine (L-ARG, 1 mmol/liter).Results Endothelium-dependent vasorelaxation was maximal with acetylocholine (ACH, 100%), followed by PRA (62.8%) and then SIM (37.1%). Direct measurement of NO confirmed that vasorelaxation is due to NO release and showed that PRA and ACH had similar dose-dependent effects on NO production, while SIM was only 25% to 30% as effective. Methemoglobin assay confirmed these results and demonstrated their specificity for NOS activity. The L-NAME blunted the responses to 45% of initial values. Excess L-ARG reversed this effect and potentiated NO production to 133% of initial levels.Conclusions Both PRA and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on eNOS activation.

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“In this context, statins increase NO availability by stimulating and upregulating endothelial NOS in vitro independent of their cholesterol-lowering actions [ 56 ].”
Background
Pravastatin down-regulates inflammatory mediators in human monocytes in vitro
Grip, O., Janciauskiene, S. M., & Lindgren, S. C. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00870-0 · Cited by 89
Early Statin Use and the Progression of Alzheimer Disease
Lin, F.-C., Chuang, Y., Hsieh, H., Lee, T.-C., Chiu, K.-F., Liu, C., & Wu, M. (2015) · Medicine · doi:10.1097/md.0000000000002143 · Cited by 94
“reduce endothelin-1, leading to vasodilatation and increase in cerebral perfusion.(6,17) In the studies of in vitro or in vivo, statin was proposed to have some neuroprotective effects through the”
Background
Statins for the prevention of Alzheimer's disease and dementia
Scott, H. D., & Laake, K. (2001) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003160 · Cited by 91
Statin therapy and angiogenesis
Skaletz‐Rorowski, A., & Walsh, K. (2003) · Current Opinion in Lipidology · doi:10.1097/00041433-200312000-00008 · Cited by 88
Statins and sepsis.
Gao, F., Linhartova, L., Johnston, A. M., & Thickett, D. R. (2008) · British Journal of Anaesthesia · doi:10.1093/bja/aem406 · Cited by 83
HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells
Skaletz‐Rorowski, A. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00618-1 · Cited by 79
Acute Reduction of Myocardial Infarct Size By a Hydroxymethyl Glutaryl Coenzyme A Reductase Inhibitor Is Mediated by Endothelial Nitric Oxide Synthase
Wolfrum, S., Grimm, M. F., Heidbreder, M., Dendorfer, A., Katus, H. A., Liao, J. K., & Richardt, G. (2003) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200303000-00017 · Cited by 77
“Statins increase eNOS expression (10,11) by stabilizing eNOS mRNA (12).”
Background
Pravastatin, A 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Renal Injury in an Experimental Model of Ischemia-Reperfusion
Joyce, M., Kelly, C. J., Winter, D. C., Chen, G., Leahy, A. L., & Bouchier‐Hayes, D. M. (2001) · Journal of Surgical Research · doi:10.1006/jsre.2001.6256 · Cited by 77
“This time period was chosen from in vivo and in vitro experiments, which showed that 72 h was a sufficient time period to enable protein production with an increase in the basal levels of ecNOS [19, 20, 46].”
BackgroundMethod
Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus
Ferderbar, S., Pereira, E. C., Apolinário, E., Bertolami, M. C., Faludi, A. Á., Monte, O., Calliari, L. E., Sales, J. E. D. S., Gagliardi, A. R. D. T., Xavier, H. T., et al. (2006) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.645 · Cited by 76
“It also leads to an increase in the activity of paraoxonase – an antioxidant enzyme linked to HDL [27] and upregulates eNOS gene expression, which increases the production of nitric oxide [28,29].”
Background
Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect
Ruiz, J. C., de Sotomayor, M. Á., Pérez‐Guerrero, C., Jimenez, L., Herrera, M. D., Pamies, E., Mv, M.-S., Stiefel, P., Miranda, M. L., Bravo, L. E., et al. (2002) · Journal of Hypertension · doi:10.1097/00004872-200203000-00018 · Cited by 75
Statins and the Role of Nitric Oxide in Chronic Heart Failure
von Haehling, S., Anker, S. D., & Bassenge, E. (2003) · Heart Failure Reviews · doi:10.1023/a:1022103222857 · Cited by 73
“For example, in vitro pravastatin appears to have an effect superior to simvastatin [ 40 ].”
Background
Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes
van Etten, R. W., de Koning, E. J. P., Honing, M. L. H., Stroes, E. S. G., Gaillard, S., & Rabelink, T. J. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000015330.64968.c4 · Cited by 72
Statin treatment depresses the fetal defence to acute hypoxia via increasing nitric oxide bioavailability
Kane, A. D., Herrera, E. A., Hansell, J. A., & Giussani, D. A. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.217968 · Cited by 70
“Normally Rho has direct negative effects on endothelial nitric oxide synthase (eNOS) mRNA activity or indirect inhibition of eNOS activity through inhibition of Akt which is known to activate eNOS through phosphorylation.”
Background
Advances in the molecular mechanisms of statins in regulating endothelial nitric oxide bioavailability: Interlocking biology between eNOS activity and L-arginine metabolism
Chen, W., Chen, C.-H., Hsu, M., Chang, R.-W., Wang, C., & Lee, T. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116192 · Cited by 70
Simvastatin Improves Diabetes-Induced Coronary Endothelial Dysfunction
Tawfik, H. E., El‐Remessy, A. B., Matragoon, S., Ma, G., Caldwell, R. B., & Caldwell, R. W. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.106823 · Cited by 70
“In addition, statins may activate eNOS by a mechanism unrelated to HMG-CoA reductase inhibition (Kaesemeyer et al., 1999; Harris et al., 2004).”
BackgroundResult
A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: Effect on inflammation, psychopathology, cognition and lipid metabolism
Vincenzi, B., Stock, S., Borba, C. P. C., Cleary, S. M., Oppenheim, C. E., Petruzzi, L. J., Fan, X., Copeland, P. M., Freudenreich, O., Cather, C., et al. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.08.021 · Cited by 67
“We chose to use pravastatin, one of the most extensively studied statins in both primary and secondary prevention trials (del Sol and Nanayakkara, 2008), available in generic form, because it appears to have fewer side effects than other statins such as simvastatin (Kaesemeyer et al., 1999; Ridker et al., 2005a, 2005b…”
BackgroundMethod
Prevention of stroke and dementia by statin therapy: Experimental and clinical evidence of their pleiotropic effects
Miida, T., Takahashi, A., & Ikeuchi, T. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.09.003 · Cited by 66
Effects of atorvastatin on reactive hyperaemia and the thrombosis–fibrinolysis system in patients with heart failure
Tousoulis, D., Antoniades, C., Bosinakou, E., Kotsopoulou, M., Tsioufis, C., Tentolouris, C., Trikas, A., Pitsavos, C., & Stefanadis, C. (2004) · Heart · doi:10.1136/hrt.2003.027110 · Cited by 66
Pluripotential Mechanisms of Cardioprotection with HMG-CoA Reductase Inhibitor Therapy
Rosenson, R. S. (2001) · American Journal of Cardiovascular Drugs · doi:10.2165/00129784-200101060-00001 · Cited by 64
Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat
de Sotomayor, M. Á., Herrera, M. D., Marhuenda, E., & Andriantsitohaina, R. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703668 · Cited by 64
“Indeed, such an e ect has been previously reported for another HMG-CoA reductase inhibitor, pravastatin (Kaesemeyer et al., 1999).”
Background
Role of L ‐arginine in the vascular actions and development of tolerance to nitroglycerin
Abou-Mohamed, G., Kaesemeyer, W., Caldwell, R. B., & Caldwell, R. W. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703293 · Cited by 63
“Pravastatin, a lipid-lowering agent, is also a vasodilator and a NOS agonist (Kaesemeyer et al., 1999).”
Background
Non—Lipid-lowering effects of statins on atherosclerosis
Rosenson, R. S. (1999) · Current Cardiology Reports · doi:10.1007/s11886-999-0027-7 · Cited by 61
Nitric oxide: an emerging role in cardioprotection?
Rakhit, R. D., & Marber, M. S. (2001) · Heart · doi:10.1136/heart.86.4.368 · Cited by 60
Short-term statin administration in hypercholesterolaemic rabbits resistant to postconditioning: effects on infarct size, endothelial nitric oxide synthase, and nitro-oxidative stress
Andreadou, I., Farmakis, D. T., Prokovas, E., Sigala, F., Ζώγα, Α., Spyridaki, K., Papalois, A. E., Papapetropoulos, A., ANASTASIOU‐NANA, M. I., Kremastinos, D. T., et al. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs121 · Cited by 60
Bioerodible devices for intermittent release of simvastatin acid
JEON, J., THOMAS, M., & Puleo, D. A. (2007) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.03.007 · Cited by 56
“Therefore, the approach used for enhancing simvastatin solubility was hydrolysis to cleave the lactone ring and convert the molecule to its β-hydroxyacid form (Kaesemeyer et al., 1999).”
MethodInfluential
Asymmetric dimethylarginine (ADMA) modulates endothelial function - therapeutic implications
Böger, R. H. (2003) · Vascular Medicine · doi:10.1191/1358863x03vm501ed · Cited by 55
The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS
Guérard, P., Rakotoniaina, Z., Goirand, F., Rochette, L., Dumas, M., Lirussi, F., & Bardou, M. (2006) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-006-0082-1 · Cited by 54
“This finding of an effect on both endothelial cells and vascular wall is in partial agreement with previous work where pravastatin increased endothelial-dependent dilation of preconstricted aortic rings, but had no effect on vascular smooth muscle cell proliferation or apoptosis (Kaesemeyer et al. 1999; Sindermann et…”
Result
Simvastatin Elicits Dilation of Isolated Porcine Retinal Arterioles: Role of Nitric Oxide and Mevalonate-Rho Kinase Pathways
Nagaoka, T., Hein, T. W., Yoshida, A., & Kuo, L. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-0856 · Cited by 54
Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition
Yamanouchi, D., Banno, H., Nakayama, M., Sugimoto, M., Fujita, H., Kobayashi, M., Kuwano, H., & Komori, K. (2005) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2005.05.041 · Cited by 53
Effects of statins on vascular function of endothelin‐1
Mraiche, F., Cena, J., Das, D., & Vollrath, B. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706114 · Cited by 53
“…enhance endothelial nitric oxide synthase (eNOS) ability to generate NO in endothelial cells, and upregulate eNOS by inhibition of geranylgeranylation of a monomeric G protein Rho, which acts as a negative regulator of the enzyme mRNA stability (Laufs & Liao, 1998; Kaesemeyer et al., 1999).”
BackgroundResult
The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease
Beishuizen, E. D., Tamsma, J. T., Jukema, J. W., van de Ree, M. A., van der Vijver, J. C. M., Meinders, A. E., & Huisman, M. V. (2005) · Diabetes Care · doi:10.2337/diacare.28.7.1668 · Cited by 52
Statins and blood pressure regulation
Borghi, C., Veronesi, M., Prandin, M. G., Dormi, A., & Ambrosioni, E. (2001) · Current Hypertension Reports · doi:10.1007/s11906-001-0090-y · Cited by 52
“This upregulation has been described in experimental conditions, particularly with pravastatin and simvastatin, and could help modulate the peripheral vascular tone regardless of the reduction in plasma cholesterol levels [ 41 ].”
Method
Oxysterol species: reliable markers of oxidative stress in diabetes mellitus
Samadi, A., Gürlek, A., Şendur, S. N., Karahan, S., Akbıyık, F., & Lay, İ. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-018-0873-5 · Cited by 51
Current Understanding on the Role of Lipids in Macrophages and Associated Diseases
Florance, I., & Seenivasan, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010589 · Cited by 51
Pravastatin Restores DDAH Activity and Endothelium-Dependent Relaxation of Rat Aorta After Exposure to Glycated Protein
Yin, Q., & Xiong, Y. (2005) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000159642.44523.7f · Cited by 50
“Similar results have been shown in normocholesterolemic subjects with coronary artery disease.(20,34) In addition to increasing synthesis of NO, the present study provides important evidence that pravastatin up-regulated vascular DDAH activity.”
Result

Authors: Kaesemeyer, W. H., Caldwell, R. B., Huang, J., & Caldwell, R. W.
Affiliations: Augusta University (US)
Corresponding author: Kaesemeyer, Wayne H.
ORCID: Kaesemeyer, Wayne H.
Caldwell, Ruth B.
Huang, Jianzhong
Caldwell, R.William
Venue: Journal of the American College of Cardiology
Publisher: Elsevier BV
Published: 1999-01
Volume: 33
Issue: 1
Pages: 234-241
ISSN: 0735-1097 (ISSN-L)
DOI: 10.1016/s0735-1097(98)00514-2
OpenAlex: W2169537677
Cited by: 343
References: 38
Citations by year: 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 8 · 2013: 10 · 2012: 9
FWCI: 19.26
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 5310 d)
Locations: Journal of the American College of Cardiology (publishedVersion)
PubMed (publishedVersion)
Funders: Bristol-Myers Squibb
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords: pravastatin, simvastatin, endothelial nitric oxide synthase, nitric oxide, endothelium-dependent relaxation, platelet aggregation, vasodilation, L-NAME, L-arginine, statins, LDL cholesterol lowering, aortic endothelial cells
MeSH terms: Animals, Anticholesteremic Agents, Cattle, Endothelium, Vascular, Enzyme Activation, Cholesterol, LDL, Male, Platelet Aggregation, Vasodilation, Pravastatin, Rats, Sprague-Dawley, Nitric Oxide Synthase, Culture Techniques, Rats, Nitric Oxide Synthase Type III

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Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions

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