Evidence for statin pleiotropy in humans

Differential effects of statins and ezetimibe on Rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation

Ping-Yen Liu, Yen-Wen Liu, Li Jen Lin, Jyh Hong Chen, James K. Liao

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

Background-By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. Methods and Results-In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R 2=-0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein. Conclusion-These results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering. (Circulation. 2009;119:131-138.)

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalCirculation
Volume119
Issue number1
DOIs
Publication statusPublished - 2009 Jan 13

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Protein Kinases
Simvastatin
Inflammation
C-Reactive Protein
LDL Cholesterol
Dilatation
Cholesterol
Placebos
Lipids
rho-Associated Kinases
Terpenes
Intestinal Absorption
Ezetimibe
Tablets
Blood Vessels
Oxidoreductases
Cardiovascular Diseases
Demography
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{6e375468405d4510b9ddb34aca54113c,
title = "Evidence for statin pleiotropy in humans: Differential effects of statins and ezetimibe on Rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation",
abstract = "Background-By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. Methods and Results-In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38{\%} and C-reactive protein by 38{\%} to 40{\%} after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R 2=-0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein. Conclusion-These results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering. (Circulation. 2009;119:131-138.)",
author = "Ping-Yen Liu and Yen-Wen Liu and Lin, {Li Jen} and Chen, {Jyh Hong} and Liao, {James K.}",
year = "2009",
month = "1",
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doi = "10.1161/CIRCULATIONAHA.108.813311",
language = "English",
volume = "119",
pages = "131--138",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
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TY - JOUR

T1 - Evidence for statin pleiotropy in humans

T2 - Differential effects of statins and ezetimibe on Rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation

AU - Liu, Ping-Yen

AU - Liu, Yen-Wen

AU - Lin, Li Jen

AU - Chen, Jyh Hong

AU - Liao, James K.

PY - 2009/1/13

Y1 - 2009/1/13

N2 - Background-By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. Methods and Results-In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R 2=-0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein. Conclusion-These results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering. (Circulation. 2009;119:131-138.)

AB - Background-By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. Methods and Results-In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R 2=-0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein. Conclusion-These results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering. (Circulation. 2009;119:131-138.)

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