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Scott D. Larsen - One of the best experts on this subject based on the ideXlab platform.
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Design and synthesis of hepatoselective, pyrrole-based HMG-CoA Reductase inhibitors.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Jeffrey A. Pfefferkorn, Yuntao Song, Kuai Lin Sun, Steven Robert Miller, Bharat K. Trivedi, Chulho Choi, Roderick J. Sorenson, Larry D. Bratton, Paul C. Unangst, Scott D. LarsenAbstract:This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA Reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA Reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.
Gene C. Ness - One of the best experts on this subject based on the ideXlab platform.
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Identification of insulin-responsive regions in the HMG-CoA Reductase promoter.
Biochemical and biophysical research communications, 2004Co-Authors: Aaron Osborne, Veronica V. Pollock, William R. Lagor, Gene C. NessAbstract:An insulin-responsive line of rat hepatoma cells, H4IIE, was used to investigate the basis for insulin's transcriptional regulation of HMG-CoA Reductase. Insulin addition to the media of these cells resulted in at least a 10-fold increase in levels of HMG-CoA Reductase protein. Adding insulin to H4IIE cells transfected with pHMGR1 (containing the proximal Reductase promoter from -270 to +20 ligated to luciferase) caused greater than 10-fold increases in luciferase activity. Transfections carried out with a series of deletion constructs identified insulin responsive regions between -203 and -130 (contains the SRE sequence) and between -85 and -105 (contains a CRE sequence). Mutation of the SRE in the -203 to -130 sequence did not decrease activation by insulin. In contrast, mutation of the C at -90 of the CRE completely eliminated the insulin response. The data suggest that insulin's activation of HMG-CoA Reductase involves the CRE in the -85 to -105 region and the -203 to -130 region of the promoter exclusive of the SRE.
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Hepatic HMG-CoA Reductase expression and resistance to dietary cholesterol.
Experimental biology and medicine (Maywood N.J.), 2004Co-Authors: Gene C. Ness, Karen R. GertzAbstract:>> The premise that the intrinsic level of expression of hepatic 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) Reductase determines the relative sensitivity to the serum cholesterol raising action of dietary cholesterol was examined in 9 strains of rat. For further comparison purposes, hamsters were also examined. The basal expression of hepatic HMG-CoA Reductase, extent of feedback regulation by cholesterol, and changes in serum cholesterol levels and the hepatic low-density lipoprotein (LDL) receptor in response to cholesterol challenge were determined in these animals. The Sprague-Dawley, Wistar-Furth, Spontaneously Hypertensive, Lewis, and WistarKyoto rats were all very resistant to dietary cholesterol and exhibited hepatic HMG-CoA Reductase activities above 150 pmol / min 1 /m g 1 . The Buffalo, Brown Norway, and Copenhagen 2331 rats had hepatic HMG-CoA Reductase activities below 90 pmol / min 1 /m g 1 and had increases in serum cholesterol levels ranging from 12 to 33 mg/dl when given a 4day, 1% cholesterol challenge. The extent of feedback regulation was reduced to only 3-fold in the Fisher 344 and Brown Norway rats that exhibited significant increases in serum cholesterol levels when given a cholesterol challenge. The Golden Syrian hamsters exhibited the largest increase (197 mg/dl) in serum cholesterol levels in response to dietary cholesterol and the lowest basal expression of hepatic HMGCoA Reductase (3.3 pmol / min 1 /m g 1 ). Hepatic LDL receptor levels were not significantly decreased by dietary cholesterol in any of the animals. The data from these inbred rats and the hamsters strongly support the conclusion that the animals expressing the highest levels of hepatic HMG-CoA Reductase are the most resistant to the serum cholesterol raising action of dietary cholesterol. Exp Biol Med 229:412–416, 2004
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Atorvastatin action involves diminished recovery of hepatic HMG-CoA Reductase activity
Journal of lipid research, 1998Co-Authors: Gene C. Ness, Christopher M. Chambers, Dayami LopezAbstract:The effects of atorvastatin on the expression of the hepatic HMG-CoA Reductase and LDL receptor genes were investigated in rats. Like the other statins, atorvastatin increased the rate of degradation and presumably cycling of the hepatic LDL receptor. In atorvastatin-treated rats, the half-life of the receptor was decreased by over 60%. Hepatic HMG-CoA Reductase mRNA levels were increased about 3-fold by feeding a diet containing 0.04% atorvastatin while Reductase protein levels were increased by as much as 700-fold. Apparent HMG-CoA Reductase activity was not increased as much as protein levels. Washing experiments revealed that atorvastatin is more difficult to remove from microsomes than lovastatin. The results support the conclusion that the potent hypocholesterolemic action of atorvastatin involves decreased hepatic VLDL production due to effective inhibition of in vivo cholesterol biosynthesis resulting from diminished recovery of HMG-CoA Reductase activity following drug treatment.
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Translational Regulation of Hepatic HMG-CoA Reductase by Dietary Cholesterol
Biochemical and biophysical research communications, 1997Co-Authors: Christopher M. Chambers, Gene C. NessAbstract:The question of whether dietary cholesterol exerts feedback regulation on hepatic HMG-CoA Reductase at the level of translation was examined by performing polysome profile analysis. Liver polysomes from rats fed 2% cholesterol in their diets for 3 days were compared with those isolated from rats fed a normal chow diet. Northern blotting analysis of the individual fractions revealed that cholesterol feeding reduced the portion of HMG-CoA Reductase mRNA associated with translationally active polysomes by over 50% and progressively increased the percentage of Reductase mRNA present in the monosomal fractions. In the lightest monosomal fraction over 10 times as much Reductase mRNA was present in samples from cholesterol animals as compared to controls. These findings indicate that dietary cholesterol exerts significant feedback regulation on hepatic HMG-CoA Reductase at the translational level.
Christopher M. Chambers - One of the best experts on this subject based on the ideXlab platform.
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Atorvastatin action involves diminished recovery of hepatic HMG-CoA Reductase activity
Journal of lipid research, 1998Co-Authors: Gene C. Ness, Christopher M. Chambers, Dayami LopezAbstract:The effects of atorvastatin on the expression of the hepatic HMG-CoA Reductase and LDL receptor genes were investigated in rats. Like the other statins, atorvastatin increased the rate of degradation and presumably cycling of the hepatic LDL receptor. In atorvastatin-treated rats, the half-life of the receptor was decreased by over 60%. Hepatic HMG-CoA Reductase mRNA levels were increased about 3-fold by feeding a diet containing 0.04% atorvastatin while Reductase protein levels were increased by as much as 700-fold. Apparent HMG-CoA Reductase activity was not increased as much as protein levels. Washing experiments revealed that atorvastatin is more difficult to remove from microsomes than lovastatin. The results support the conclusion that the potent hypocholesterolemic action of atorvastatin involves decreased hepatic VLDL production due to effective inhibition of in vivo cholesterol biosynthesis resulting from diminished recovery of HMG-CoA Reductase activity following drug treatment.
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Translational Regulation of Hepatic HMG-CoA Reductase by Dietary Cholesterol
Biochemical and biophysical research communications, 1997Co-Authors: Christopher M. Chambers, Gene C. NessAbstract:The question of whether dietary cholesterol exerts feedback regulation on hepatic HMG-CoA Reductase at the level of translation was examined by performing polysome profile analysis. Liver polysomes from rats fed 2% cholesterol in their diets for 3 days were compared with those isolated from rats fed a normal chow diet. Northern blotting analysis of the individual fractions revealed that cholesterol feeding reduced the portion of HMG-CoA Reductase mRNA associated with translationally active polysomes by over 50% and progressively increased the percentage of Reductase mRNA present in the monosomal fractions. In the lightest monosomal fraction over 10 times as much Reductase mRNA was present in samples from cholesterol animals as compared to controls. These findings indicate that dietary cholesterol exerts significant feedback regulation on hepatic HMG-CoA Reductase at the translational level.
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Farnesol Is Not the Nonsterol Regulator Mediating Degradation of HMG-CoA Reductase in Rat Liver
Archives of biochemistry and biophysics, 1996Co-Authors: R. K. Keller, Zhihong Zhao, Christopher M. ChambersAbstract:Abstract A recent report, in which cultured tumor cells were used, identified farnesol as the nonsterol mevalonate-derived metabolite required for the accelerated degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) Reductase (C. C. Correll, L. Ng, and P. A. Edwards, 1994, J. Biol. Chem. 269, 17390–17393). We examined this proposed linkage in animals by measuring hepatic farnesol levels and rates of HMG-CoA Reductase degradation under conditions previously shown to alter the stability of the Reductase. In normal rats, the hepatic farnesol level, quantified by high-pressure liquid chromatography, was 0.10 ± 0.08 μg/g and the half-life of HMG-CoA Reductase was 2.5 h. Administration of mevalonolactone at 1 g/kg body wt to provide all nonsterol metabolites in addition to cholesterol increased farnesol levels 6-fold without significantly affecting the half-life of the Reductase. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, raised hepatic farnesol levels 10-fold and decreased the half-life of HMG-CoA Reductase to 0.25 h. However, feeding lovastatin to rats did not lower hepatic farnesol levels despite a marked stabilization of HMG-CoA Reductase protein. Moreover, intubation of rats with 500 mg/kg body wt of farnesol failed to decrease the half-life of HMG-CoA Reductase protein, alter the levels of enzyme activity, or change of the levels of immunoreactive protein despite an increase of 1000-fold in hepatic farnesol levels. These observations indicate that farnesol per se does not induce accelerated degradation of HMG-CoA Reductase in rat liver.
Rune Dahlqvist - One of the best experts on this subject based on the ideXlab platform.
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HMG-CoA Reductase Inhibitors and Myotoxicity
Drug Safety, 2000Co-Authors: Memduh Ucar, Tom Mjörndal, Rune DahlqvistAbstract:The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) Reductase inhibitors specifically inhibit HMG-CoA Reductase in the liver, thereby inhibiting the biosynthesis of cholesterol. These drugs significantly reduce plasma cholesterol level and long term treatment reduces morbidity and mortality associated with coronary heart disease. The tolerability of these drugs during long term administration is an important issue. Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug. Occasionally, arthralgia, alone or in association with myalgia, has been reported. In this article we review scientific data provided via Medline, adverse drug reaction case reports from the Swedish Drug Information System (SWEDIS) and the World Health Organization’s International Drug Information System (INTDIS) database, focusing on HMG-CoA Reductase inhibitor-related musculoskeletal system events. Cytochrome P450 (CYP) 3A4 is the main isoenzyme involved in the metabolic transformation of HMG-CoA Reductase inhibitors. Individuals with both low hepatic and low gastrointestinal tract levels of CYP3A4 expression may be at in increased risk of myotoxicity due to potentially higher HMG-CoA Reductase inhibitor plasma concentrations. The reported incidence of myotoxic reactions in patients treated with this drug class varies from 1 to 7% and varies between different agents. The risk of these serious adverse reactions is dose-dependent and may increase when HMG-CoA Reductase inhibitors are prescribed concomitantly with drugs that inhibit their metabolism, such as itraconazole, cyclosporin, erythromycin and nefazodone. Electrolyte disturbances, infections, major trauma, hypoxia as well as drugs of abuse may increase the risk of myotoxicity. It is important that the potentially serious adverse reactions are recognised and correctly diagnosed so that the HMG-CoA Reductase inhibitor may at once be withdrawn to prevent further muscular damage.
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HMG-CoA Reductase inhibitors and myotoxicity.
Drug safety, 2000Co-Authors: Memduh Ucar, Tom Mjörndal, Rune DahlqvistAbstract:The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) Reductase inhibitors specifically inhibit HMG-CoA Reductase in the liver, thereby inhibiting the biosynthesis of cholesterol. These drugs significantly reduce plasma cholesterol level and long term treatment reduces morbidity and mortality associated with coronary heart disease.
Robert S. Rosenson - One of the best experts on this subject based on the ideXlab platform.
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Pluripotential Mechanisms of Cardioprotection with HMG-CoA Reductase Inhibitor Therapy
American Journal of Cardiovascular Drugs, 2001Co-Authors: Robert S. RosensonAbstract:Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) Reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA Reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA Reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA Reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques. Treatment with HMG-CoA Reductase inhibitors improved endothelial dysfunction in patients with hypercholesterolemia and this improvement in endothelial function was not correlated with reduction in total serum cholesterol levels. Similarly, reduction in endothelial pre-proendothelin mRNA expression and endothelin synthesis and blood pressure lowering with HMG-CoA Reductase inhibitors occurred independent of lipid-lowering. Finally, HMG-CoA Reductase inhibitors increased endothelial nitric oxide levels i. e. upregulated endothelial nitric oxide synthetase expression via post-transcriptional mechanisms and prevented its down-regulation by oxidized LDL-C. HMG-CoA Reductase inhibitors have been shown to modulate the immune response by inhibiting activation of immune-competent cells such as macrophages, and antigen presentation to macrophages by T cells. Treatment with HMG-CoA Reductase inhibitors can reduce expression, production and circulating levels of chemokines (monocyte chemoattractant protein-1) and proinflammatory cytokines [tumor necrosis factorα, interleukin (IL)-6 and IL-1β]. HMG-CoA Reductase inhibitors reduced inflammation in human atheroma: significantly fewer macrophages and T cells, less oxidized LDL-C and higher collagen content. In addition, treatment with HMG-CoA Reductase inhibitor led to decreased cell death within the atheroma. Treatment with these agents also reduced expression of inducible cellular adhesion molecules, decreased secretion of metalloproteinases by macrophages, reduced vascular smooth muscle cell apoptosis. Lastly, HMG-CoA Reductase inhibitors appear to have important effects on the thrombogenesis: reduced expression of tissue factor production and activity; increased production of tissue factor package inhibitor; decreased platelet thrombus formation and improved fibrinolysis as a result of lowered plasminogen activator inhibitor-1 levels. As the pluripotential cardioprotective mechanisms of HMG-CoA Reductase inhibitors are further elucidated, it is envisaged that treatment with HMG-CoA Reductase inhibitors will be initiated earlier and more frequently in patients with hypercholesterolemia.
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Pluripotential Mechanisms of Cardioprotection with HMG-CoA Reductase Inhibitor Therapy
American journal of cardiovascular drugs : drugs devices and other interventions, 2001Co-Authors: Robert S. RosensonAbstract:Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) Reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA Reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA Reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA Reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques.