A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins

Goldstein, Joseph L.; Brown, Michael S.

doi:10.1016/j.cell.2015.01.036

Cited by 927 publications

(727 citation statements)

References 101 publications

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“…At cellular and molecular levels, simvastatin increases endothelial nitric oxide (eNOS) activity and leads to NO production in endothelial cells (ECs) by regulating a kinase‐dependent pathway and protein‐protein interaction 6, 7. Despite many achievements of statins in treating cardiovascular complications,3, 8, 9, 10 such treatment is not always effective in improving EC function and inflammation, with unclear mechanisms under some circumstances 11, 12. Recently, asymmetric dimethylarginine (ADMA) has been implicated as a contributing factor to the lack of protective effect of statins 13, 14…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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“…Epidemiological studies have found an association between blood lipoprotein concentrations and the risk of heart attack 4 , and human genetic studies and randomized trials suggest that LDL is one causal factor 5 . Some evidence, particularly analyses of proteins that clear TRLs from the blood, suggests that TRLs also contribute to the risk of heart attack 4 .…”

Section: S E K a R K At H I R E S A Nmentioning

confidence: 99%

“…Possible culprits 5 include compounds known as methane hydrates, found in deep-sea sediments; volcanism that coincided with the initial opening of the Norwegian-Greenland Sea; and thawing of permafrost. Quantifying the magnitude, origin and emission rates of carbon is important.…”

Section: K At R I N J M E I S S N E R and T I M O T H Y J B R A L Omentioning

confidence: 99%

Putative medicines that mimic mutations

Kathiresan

2017

Nature

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“…Therefore, CHD is the leading cause of death in diabetic patients. [4][5][6] Many factors contribute to the increased rate of atherosclerosis progression in diabetes, including alterations in plasma lipid profile, platelet function, clotting factors, metabolism of arterial wall cells, and elevated blood pressure. The precise mechanisms of premature atherogenesis in diabetic patients, however, remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…[7] Low-density lipoprotein (LDL) has been associated with sourcing of accumulating lipids. [6,8,9] However, LDL isolated from healthy individuals failed to produce notable cholesterol accumulation in cultured arterial smooth muscle cells or macrophages. [10,11] It was hence accepted that LDL is required to undergo structural alterations or chemical modifications to become atherogenic.…”

Section: Introductionmentioning

confidence: 99%

Small dense and desialylated low density lipoprotein in diabetic patients

Sobenin¹,

Galitsyna²,

Grechko³

et al. 2017

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How to cite this article: Sobenin IA, Galitsyna EV, Grechko AV, Orekhov AN. Small dense and desialylated low density lipoprotein in diabetic patients. Vessel Plus 2017;1:29-37.Aim: This study was undertaken to investigate the physicochemical properties of modified low density lipoprotein (LDL) in diabetes. Methods: LDL from 10 type 1 and 10 type 2 diabetic patients, as well as LDL from 10 non-diabetic subjects, was subdivided into bound and nonbound fractions by affinity chromatography on Ricinus communis agglutinin-agarose, and further characterized by sialic acid content, hydrated density, electrophoretic mobility, and the ability to induce cholesterol deposition in cultured cells. Results: The non-bound LDL fraction was similar to native LDL from healthy subjects, with respect to its physicochemical properties, and did not produce intracellular cholesterol accumulation. The bound LDL fraction was characterized by several alterations differentiating it from non-bound LDL, namely, significantly lowered sialic acid content (by 35-50%, compared with non-bound LDL), increased electrophoretic mobility (by 40-50%), increased hydrated density (difference in modae, 5.6-5.9 mg/mL), and smaller particle size (difference in modae, 3.8-4.9 nm). Bound LDL possessed the ability to induce a 2.1-to 2.7-fold increase in intracellular cholesterol content. Conclusion: The results showed the presence of a dense, small, more electronegative, desialylated LDL subfraction in the blood of diabetic patients, which is in vivo modified atherogenic LDL.

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A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins

Cited by 927 publications

References 101 publications

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Putative medicines that mimic mutations

Small dense and desialylated low density lipoprotein in diabetic patients

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