Cholesterol-independent Effects of Statins and New Therapeutic Targets: Ischemic Stroke and Dementia

Miida, Takashi; Hirayama, Satoshi; Nakamura, Yūichi

doi:10.5551/jat.11.253

Cited by 92 publications

(74 citation statements)

References 95 publications

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“…Another study demonstrated that statin therapy is associated with reduced rates of plaque progression among individuals with asymptomatic carotid atherosclerosis (24). Because statins exhibit a variety of cholesterol-independent, plaque-stabilizing effects involved in endothelial function, cell proliferation, inflammatory response, and lipid oxidation, they might ultimately affect 18 F-sodium fluoride uptake (25). However, in the present study it could not be demonstrated that statin therapy significantly affected tracer uptake.…”

Section: Comparison To Other Pet Tracers and Cardiovascular Risk Factorscontrasting

confidence: 54%

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using ¹⁸F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

Derlin¹,

Wisotzki²,

Richter³

et al. 2011

J Nucl Med

150

111

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The purpose of this study was to correlate 18 F-sodium fluoride accumulation in the common carotid arteries of neurologically asymptomatic patients with cardiovascular risk factors and carotid calcified plaque burden. Methods: Two hundred sixtynine oncologic patients were examined by 18 F-sodium fluoride PET/CT. Tracer accumulation in the common carotid arteries was analyzed both qualitatively and semiquantitatively by measuring the blood-pool-corrected standardized uptake value (target-to-background ratio) and comparing it with cardiovascular risk factors and calcified plaque burden. Results: 18 Fsodium fluoride uptake was observed at 141 sites in 94 (34.9%) patients. Radiotracer accumulation was colocalized with calcification in all atherosclerotic lesions. 18 F-sodium fluoride uptake was significantly associated with age (P , 0.0001), male sex (P , 0.0001), hypertension (P , 0.002), and hypercholesterolemia (P , 0.05). The presence of calcified plaque correlated significantly with these risk factors but also with diabetes (P , 0.0001), history of smoking (P 5 0.03), and prior cardiovascular events (P , 0.01). There was a highly significant correlation between the presence of 18 F-sodium fluoride uptake and number of present cardiovascular risk factors (r 5 0.30, P , 0.0001). Conclusion: Carotid 18 F-sodium fluoride uptake is a surrogate measure of calcifying carotid plaque, correlates with cardiovascular risk factors, and is more frequent in patients with a high-risk profile for atherothrombotic events but demonstrates a weaker correlation with risk factors than does calcified plaque burden. This study provides a rationale to conduct further prospective studies to determine whether 18 F-sodium fluoride uptake can predict vascular events, or if it may be used to monitor pharmacologic therapy.

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Section: Comparison To Other Pet Tracers and Cardiovascular Risk Factorscontrasting

confidence: 54%

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using ¹⁸F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

Derlin¹,

Wisotzki²,

Richter³

et al. 2011

J Nucl Med

150

111

View full text Add to dashboard Cite

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“…A specific group of drugs, known as statins, competitively block enzymatic activity of HMGR (30). Many studies have shown that statins have a multitude of other actions, being involved in endothelial function, cell proliferation, inflammatory responses, immunological reactions, platelet function, and lipid oxidation (31). Although statins efficiently reduce serum cholesterol levels, recent research indicates that statins affect not only synthesis of cholesterol, but also, through inhibition of HMGR, affect other intermediates in the cholesterol pathway and, thus, may lead to many undesirable effects.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression

Villagra

Ulloa

Zhang

et al. 2007

Journal of Biological Chemistry

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In vertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/ rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochemical functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that histone deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concentrations compared with parental cells. Extensive promoter analyses coupled with chromatin immunoprecipitation assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated.Cholesterol, cholesterol metabolites, and biosynthetic precursors of cholesterol play essential roles in cellular membrane physiology, dietary nutrient absorption, reproductive biology, stress responses, salt and water balance, and calcium metabolism (1). Although important for many normal cellular functions, cholesterol can have negative effects when it reaches excess concentrations, contributing to several diseases (2), of which the most notable is atherosclerosis.Cellular cholesterol homeostasis is achieved by influx and efflux and intracellular transport as well as by regulation of cholesterol synthesis (3). The rate-limiting enzyme in cholesterol synthesis is HMG-CoA reductase (HMGR), 2 and high cholesterol accelerates degradation of HMGR (4). Another mechanism in the regulation of cholesterol synthesis involves the membrane-bound transcription factors sterol regulatory element-binding proteins (SREBPs). The promoters of sterolregulated genes contain a sterol response element. SREBPs are synthesized as transcriptionally inactive endoplasmic reticulum transmembrane proteins. At high cholesterol levels within the cell, SREBPs remain in the endoplasmic reticulum in association with two proteins, SCAP and Insig (5). A decrease in cholesterol levels causes a conformational change in th...

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“…The antioxidative effect exhibited by both drugs is considered to be one of the mechanisms behind the anti-atherogenic effect. To demonstrate the antioxidative effect of both drugs, the oxidized lipid reducing effect has been mainly studied (11,12,18). However, whether probucol and statins suppress systemic oxidative stress in diabetic patients is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

“…Probucol and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) were developed as cholesterol-lowering agents and found to have antioxidative effects (8)(9)(10)(11)(12). Probucol has been reported to reduce carotid artery intima-media thickness (13) and prevent restenosis after percutaneous transluminal coronary angioplasty (14).…”

Section: Introductionmentioning

confidence: 99%

Probucol and Atorvastatin Decrease Urinary 8-Hydroxy-2'-deoxyguanosine in Patients with Diabetes and Hypercholesterolemia

Endo

Miyashita

Sasaki

et al. 2006

JAT

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To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total-and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 ± ± ± ± ± 7.5 to 8.1 ± ± ± ± ± 4.2 ng/ mg/Cr in the atorvastatin group (p < 0.05) and 12.3 ± ± ± ± ± 8.8 to 6.8 ± ± ± ± ± 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 ± ± ± ± ± 4.9 to 9.2 ± ± ± ± ± 3.4 ng/ mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 ± ± ± ± ± 8.2 to 6.67 ± ± ± ± ± 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress. J Atheroscler Thromb, 2006; 13: 68-75.

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Cholesterol-independent Effects of Statins and New Therapeutic Targets: Ischemic Stroke and Dementia

Cited by 92 publications

References 95 publications

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using ¹⁸F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using ¹⁸F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression

Probucol and Atorvastatin Decrease Urinary 8-Hydroxy-2'-deoxyguanosine in Patients with Diabetes and Hypercholesterolemia

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Cholesterol-independent Effects of Statins and New Therapeutic Targets: Ischemic Stroke and Dementia

Cited by 92 publications

References 95 publications

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using 18F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using 18F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression

Probucol and Atorvastatin Decrease Urinary 8-Hydroxy-2'-deoxyguanosine in Patients with Diabetes and Hypercholesterolemia

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Product

Resources

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In Vivo Imaging of Mineral Deposition in Carotid Plaque Using ¹⁸F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using ¹⁸F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors