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Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.
Jerome RN, Pulley JM, Roden DM, Shirey-Rice JK, Bastarache LA, R Bernard G, B Ekstrom L, Lancaster WJ, Denny JC
(2018) Drug Saf 41: 303-311
MeSH Terms: Cholesterol, LDL, Enzyme Inhibitors, Female, Genotype, Humans, Hypercholesterolemia, Male, Phenotype, Polymorphism, Single Nucleotide, Product Surveillance, Postmarketing, Proprotein Convertase 9, Risk Factors, Spinal Dysraphism
Show Abstract · Added March 14, 2018
INTRODUCTION - When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities.
OBJECTIVE - We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9).
METHODS - Using phenome-wide association study (PheWAS) methods, we analyzed available genotype and clinical data from 29,722 patients, leveraging the known effects of changes in PCSK9 to identify novel phenotypes in which this protein and its inhibitors may have impact.
RESULTS - PheWAS revealed a significantly reduced risk of hypercholesterolemia (odds ratio [OR] 0.68, p = 7.6 × 10) in association with a known loss-of-function variant in PCSK9, R46L. Similarly, laboratory data indicated significantly reduced beta mean low-density lipoprotein cholesterol (- 14.47 mg/dL, p = 2.58 × 10) in individuals carrying the R46L variant. The R46L variant was also associated with an increased risk of spina bifida (OR 5.90, p = 2.7 × 10), suggesting that further investigation of potential connections between inhibition of PCSK9 and neural tube defects may be warranted.
CONCLUSION - This novel methodology provides an opportunity to put in place new mechanisms to assess the safety and long-term tolerability of PCSK9 inhibitors specifically, and other new agents in general, as they move into human testing and expanded clinical use.
0 Communities
2 Members
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13 MeSH Terms
Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice.
Babaev VR, Yeung M, Erbay E, Ding L, Zhang Y, May JM, Fazio S, Hotamisligil GS, Linton MF
(2016) Arterioscler Thromb Vasc Biol 36: 1122-31
MeSH Terms: Animals, Aorta, Aortic Diseases, Apoptosis, Atherosclerosis, Bone Marrow Cells, Bone Marrow Transplantation, Cell Survival, Cells, Cultured, Diet, High-Fat, Disease Models, Animal, Endoplasmic Reticulum Stress, Genetic Predisposition to Disease, Hypercholesterolemia, Macrophages, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, PTEN Phosphohydrolase, Phenotype, Plaque, Atherosclerotic, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Receptors, LDL, Signal Transduction, bcl-Associated Death Protein
Show Abstract · Added April 10, 2018
OBJECTIVE - The c-Jun NH2-terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis.
APPROACH AND RESULTS - To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr(-/-) mice were reconstituted with wild-type, Jnk1(-/-), and Jnk2(-/-) hematopoietic cells and fed a high cholesterol diet. Jnk1(-/-)→Ldlr(-/-) mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2(-/-) cells. Moreover, genetic ablation of JNK to a single allele (Jnk1(+/-)/Jnk2(-/-) or Jnk1(-/-)/Jnk2(+/-)) in marrow of Ldlr(-/-) recipients further increased atherosclerosis compared with Jnk1(-/-)→Ldlr(-/-) and wild-type→Ldlr(-/-) mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1(-/-) macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways.
CONCLUSIONS - Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.
© 2016 American Heart Association, Inc.
0 Communities
1 Members
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MeSH Terms
Cardiology Patient Page. ABCDE Steps for Heart and Vascular Wellness Following a Prostate Cancer Diagnosis.
Guan J, Khambhati J, Jones LW, Morgans A, Allaf M, Penson DF, Moslehi J
(2015) Circulation 132: e218-20
MeSH Terms: Adenocarcinoma, Androgen Antagonists, Androgens, Antineoplastic Agents, Hormonal, Cardiovascular Diseases, Comorbidity, Diabetes Mellitus, Diet, Disease Susceptibility, Exercise, Health Promotion, Humans, Hypercholesterolemia, Hypertension, Life Style, Male, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Risk Factors, Smoking Cessation, Survivors
Added February 4, 2016
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2 Members
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21 MeSH Terms
Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL.
Tavori H, Su YR, Yancey PG, Giunzioni I, Wilhelm AJ, Blakemore JL, Zabalawi M, Linton MF, Sorci-Thomas MG, Fazio S
(2015) J Lipid Res 56: 635-643
MeSH Terms: Animals, Apolipoprotein A-I, Atherosclerosis, B-Lymphocytes, CD4-Positive T-Lymphocytes, Dendritic Cells, Dermatitis, Gene Expression Regulation, Humans, Hypercholesterolemia, Lipoproteins, HDL, Macrophages, Mice, Mice, Knockout
Show Abstract · Added January 20, 2015
Tissue cholesterol accumulation, macrophage infiltration, and inflammation are features of atherosclerosis and some forms of dermatitis. HDL and its main protein, apoAI, are acceptors of excess cholesterol from macrophages; this process inhibits tissue inflammation. Recent epidemiologic and clinical trial evidence questions the role of HDL and its manipulation in cardiovascular disease. We investigated the effect of ectopic macrophage apoAI expression on atherosclerosis and dermatitis induced by the combination of hypercholesterolemia and absence of HDL in mice. Hematopoietic progenitor cells were transduced to express human apoAI and transplanted into lethally irradiated LDL receptor(-/-)/apoAI(-/-) mice, which were then placed on a high-fat diet for 16 weeks. Macrophage apoAI expression reduced aortic CD4(+) T-cell levels (-39.8%), lesion size (-25%), and necrotic core area (-31.6%), without affecting serum HDL or aortic macrophage levels. Macrophage apoAI reduced skin cholesterol by 39.8%, restored skin morphology, and reduced skin CD4(+) T-cell levels. Macrophage apoAI also reduced CD4(+) T-cell levels (-32.9%) in skin-draining lymph nodes but had no effect on other T cells, B cells, dendritic cells, or macrophages compared with control transplanted mice. Thus, macrophage apoAI expression protects against atherosclerosis and dermatitis by reducing cholesterol accumulation and regulating CD4(+) T-cell levels, without affecting serum HDL or tissue macrophage levels.
Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
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3 Members
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14 MeSH Terms
From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production.
Harrison DG
(2014) J Clin Invest 124: 473-5
MeSH Terms: Animals, Biomedical Research, Clinical Trials as Topic, Coronary Vasospasm, Endothelium, Vascular, History, 20th Century, History, 21st Century, Humans, Hypercholesterolemia, Inflammation, Oxidative Stress, Reactive Oxygen Species, Superoxides, Vascular Diseases
Show Abstract · Added March 31, 2015
As a young medical resident, I encountered a patient suffering from spontaneous coronary vasospasm and was puzzled by these dramatic alterations in vasomotion. This encounter piqued my interest in understanding the drivers of vascular reactivity. In a paper published in the JCI, my colleagues and I revealed a role for superoxide production in the vascular dysfunction associated with hypercholesterolemia. Subsequent work by our group and others has unveiled complex associations between ROS generation and vascular disease.
1 Communities
1 Members
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14 MeSH Terms
Impaired liver regeneration in Ldlr-/- mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids.
Pauta M, Rotllan N, Vales F, Fernandez-Hernando A, Allen RM, Ford DA, Marí M, Jiménez W, Baldán A, Morales-Ruiz M, Fernández-Hernando C
(2013) J Hepatol 59: 731-7
MeSH Terms: Animals, Cell Cycle Checkpoints, Cholesterol, Fatty Liver, Hepatectomy, Hepatocyte Growth Factor, Hypercholesterolemia, Interleukin-6, Lipid Metabolism, Liver, Liver Regeneration, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL, Signal Transduction, Tumor Necrosis Factor-alpha
Show Abstract · Added February 12, 2016
BACKGROUND & AIMS - It is widely recognized that in the early stages of liver regeneration after partial hepatectomy, the hepatocytes accumulate a significant amount of lipids. The functional meaning of this transient steatosis and its effect on hepatocellular proliferation are not well defined. In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr).
METHODS - To address these questions, we studied the process of liver regeneration in Ldlr null mice and wild type mice following partial hepatectomy.
RESULTS - Ldlr deficiency was associated with a significant decrease in serum albumin concentration, during early stages of liver regeneration, and a delayed hepatic regeneration. Remnant livers of Ldlr(-)(/)(-) showed a time-shifted expression of interleukin-6 (IL6) and a defective activation of tumor necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) expression in early phases of liver regeneration. Unexpectedly, Ldlr(-)(/)(-) showed no significant differences in the content of lipid droplets after partial hepatectomy compared to wild type mice. However, lipidomic analysis of the regenerating liver from Ldlr(-)(/)(-) revealed a lipid profile compatible with liver quiescence: high content of cholesterol esters and ceramide, and low levels of phosphatidylcholine.
CONCLUSIONS - Ldlr deficiency is associated with significant changes in the hepatic lipidome that affect cytokine-growth factor signaling and impair liver regeneration. These results suggest that the analysis of the hepatic lipidome may help predict the success of liver regeneration in the clinical environment, specifically in the context of pre-existing liver steatosis.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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1 Members
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18 MeSH Terms
Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation.
Tavori H, Fan D, Blakemore JL, Yancey PG, Ding L, Linton MF, Fazio S
(2013) Circulation 127: 2403-13
MeSH Terms: Animals, Cells, Cultured, Cholesterol, Disease Models, Animal, Humans, Hypercholesterolemia, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Serine Endopeptidases, Transfection
Show Abstract · Added December 10, 2013
BACKGROUND - Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.
METHODS AND RESULTS - To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely because of the impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apolipoprotein B-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine PCSK9 levels by 4.3-fold in wild-type mice and not at all in LDLR(-/-) mice, in which murine PCSK9 levels were already 10-fold higher than in wild-type mice. In addition, LDLR(+/-) mice had a 2.7-fold elevation in murine PCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of human LDLR in transgenic mice caused a 70% decrease in serum murine PCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in wild-type mice (half-life, 5.2 minutes), faster clearance in human LDLR transgenics (2.9 minutes), and much slower clearance in LDLR(-/-) recipients (50.5 minutes). Supportive results were obtained with an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.
CONCLUSIONS - Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
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1 Members
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17 MeSH Terms
Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver.
Liu Y, Major AS, Zienkiewicz J, Gabriel CL, Veach RA, Moore DJ, Collins RD, Hawiger J
(2013) J Am Heart Assoc 2: e000093
MeSH Terms: Active Transport, Cell Nucleus, Animals, Atherosclerosis, Cell Nucleus, Cell-Penetrating Peptides, Cholesterol, Dietary Fats, Disease Models, Animal, Fatty Liver, Female, Hypercholesterolemia, Liver, Mice, Mice, Transgenic, NF-kappa B, Peptides, Sterol Regulatory Element Binding Proteins, Transcription Factors, Triglycerides
Show Abstract · Added February 11, 2014
BACKGROUND - Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide.
METHODS AND RESULTS - A cell-penetrating nuclear transport modifier (NTM) reduced hyperlipidemia, atherosclerosis, and fatty liver in low-density lipoprotein receptor-deficient mice fed a Western diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P<0.005) and liver (41% and 34%, respectively; P<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (P<0.0005), and liver function improved compared with saline-treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (P<0.005), and body weight gain was ameliorated (P<0.005) in NTM-treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress-responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element-binding protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM-modulated translocation of SREBPs to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia.
CONCLUSIONS - Two-pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications.
1 Communities
4 Members
0 Resources
19 MeSH Terms
Nicotinic acetylcholine receptor α1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy.
Zhang G, Thomas AL, Marshall AL, Kernan KA, Su Y, Zheng Y, Takano J, Saido TC, Eddy AA
(2011) Lab Invest 91: 106-23
MeSH Terms: Actins, Animals, Antigens, Differentiation, Apolipoproteins E, Blotting, Northern, Blotting, Western, Calcium-Binding Proteins, Calpain, Cell Line, Female, Hypercholesterolemia, Inflammation, Kidney, Kidney Diseases, Macrophages, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Nephrectomy, RNA Interference, Receptors, Nicotinic, Transforming Growth Factor beta1
Show Abstract · Added February 3, 2012
The nicotinic acetylcholine receptor α1 (nAChRα1) was investigated as a potential proinflammatory molecule in the kidney, given a recent report that it is an alternative urokinase plasminogen activator (uPA) receptor, in addition to the classical receptor uPAR. Two animal models and in vitro monocyte studies were involved: (1) In an ApoE(-/-) mouse model of chronic kidney disease, glomerular-resident cells and monocytes/macrophages were identified as the primary cell types that express nAChRα1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChRα1 gene for 4 months (6 months on Western diet) prevented the increases in renal monocyte chemoattractant protein-1 and osteopontin expression levels and F4/80+ macrophage infiltration compared with the nonsilenced mice. These changes were associated with significantly reduced transforming growth factor-β1 mRNA (50% decrease) and α smooth muscle actin-positive (αSMA+) myofibroblasts (90% decrease), better glomerular and tubular basement membranes (GBM/TBM) preservation (threefold less disintegration), and better renal function preservation (serum creatinine 40% lower) in the nAChRα1-silenced mice. The nAChRα1 silencing was also associated with significantly reduced renal tissue calcium deposition (78% decrease) and calpain-1 (but not calpain-2) activation (70% decrease). (2) The nAChRα1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChRα1 significantly reduced both calpain-1 and -2 activities, and reduced the degradation of the calpain substrate talin. (3) To further explore the role of calpain-1 activity in hypercholesterolemic nephropathy, disease severities were compared in CAST(-/-)ApoE(-/-) (calpain overactive) mice and ApoE(-/-) mice fed with Western diet for 10 months (n=12). Macrophages were the main cell type of renal calpain-1 production in the model. The number of renal F4/80+ macrophages was 10-fold higher in the CAST(-/-)ApoE(-/-) mice (P<0.05), and was associated with a significantly higher level of αSMA+ cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChRα1 is an important regulator of calpain-1 activation and inflammation in the chronic hypercholesterolemic nephropathy. This new proinflammatory pathway may also be relevant to other disorders beyond hyperlipidemic nephropathy.
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1 Members
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25 MeSH Terms
Statins for acutely hospitalized patients: randomized controlled trials are long overdue.
Bernard GR
(2010) Crit Care 14: 141
MeSH Terms: Critical Illness, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Inpatients, Randomized Controlled Trials as Topic, Survival Analysis
Show Abstract · Added March 5, 2014
From the earliest studies of statins for control of plasma cholesterol, observations have been made that the reductions in mortality observed occurred in a manner seemingly independent from what could be anticipated from cholesterol lowering alone. Over the last decade, the pleiotropic effects of statins have been increasingly elucidated. Perhaps most intriguing are the effects statins appear to have on the immune system, especially the modulation of diffuse or systemic inflammation. There is a growing body of observational literature suggesting that statins can actually reduce hospital mortality through mechanisms far beyond those that can be explained by reductions in cardiovascular events.
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7 MeSH Terms