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Am J Cardiol. 2006 Dec 15;98(12):1656-9. Epub 2006 Oct 25
Hernandez TL, Capell WH, Wolfe P, Gerard LA, Eckel RH.
Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver & Health Sciences Center, Denver, Colorado.
Time course of C-reactive protein reduction with simvastatin therapy in patients with type 2 diabetes mellitus.
A research was conducted recently to study the time course of C-reactive protein decrease with simvastatin therapy in type 2 diabetes mellitus patients. Treatment was conducted for 28 days. The researchers concluded that simvastatin is more effective than any other medication available.
The aim of this study was to investigate the time course of C-reactive protein (CRP) reduction with simvastatin in patients with type 2 diabetes mellitus. Thirty-five subjects (mean +/- SEM body mass index 32.8 +/- 1 kg/m(2), mean +/- SEM glycated hemoglobin 7.3 +/- 0.2%) were studied using a randomized, crossover, double-blind design. Patients were treated with simvastatin 40 mg or placebo for 28 days, with a minimum 28-day intervening washout. On entry, all subjects had low-density lipoprotein cholesterol >100 mg/dl and/or non-high-density lipoprotein cholesterol >130 mg/dl. High-sensitivity CRP (hs-CRP) was measured on days 0, 1, 3, 7, 14, 21, and 28 of each phase; fasting lipids were measured weekly. The mean hs-CRP level was 4.2 +/- 0.6 mg/L at baseline (>3.0 mg/L represents high risk). After simvastatin administration, there was a significant reduction in levels of log(hs-CRP) (p = 0.001). This effect of simvastatin was seen by day 7 (p = 0.008), with maximal reduction seen at day 14 (p = 0.004; hs-CRP in original units 3.1 +/- 0.5 mg/L with simvastatin and 4.1 +/- 0.6 mg/L with placebo). As expected, the change in hs-CRP was not related to low-density lipoprotein cholesterol reduction. By day 28 with simvastatin, hs-CRP had returned to near baseline levels. In conclusion, in patients with type 2 diabetes mellitus, simvastatin reduced hs-CRP within 7 days. However, this potentially beneficial effect was lost within 28 days.
J Cereb Blood Flow Metab. 2005 Feb 16
Asahi M, Huang Z, Thomas S, Yoshimura SI, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA.
1Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia.
A study on the Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. Statins have the capability to increase eNOS and tPA mRNA levels without changing the mRNA levels of PAI-1. The study proved that statins protect against stroke by multiple mechanisms involving both eNOS and tPA.
Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wild-type mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.Journal of Cerebral Blood Flow & Metabolism advance online publication, 16 February 2005; doi:10.1038/sj.jcbfm.9600070.
FASEB J. 2005 Feb 23
Turner NA, Oregan DJ, Ball SG, Porter KE.
Simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels.
A study was conducted to find out whether statins inhibit MMP-9 secretion from cultured human SV smooth muscle cells (SMC) and examined the underlying mechanisms. Here the authors suggests that simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells. It can inhibit the RhoA/ROCK pathway and reducing MMP-9 mRNA levels.
Increased matrix metalloproteinase-9 (MMP-9) expression is associated with intimal hyperplasia in saphenous vein (SV) bypass grafts. Recent evidence suggests that HMG-CoA reductase inhibitors (statins) can prevent the progression of vein graft failure. Here we investigated whether statins inhibited MMP-9 secretion from cultured human SV smooth muscle cells (SMC) and examined the underlying mechanisms. SV-SMC from different patients were exposed to phorbol ester (TPA) or PDGF-BB plus interleukin-1alpha (IL-1). MMP-9 secretion and mRNA expression were analyzed using gelatin zymography and RT-PCR, respectively. Specific signal transduction pathways were investigated by immunoblotting and pharmacological inhibition. Simvastatin reduced TPA- and PDGF/IL-1-induced MMP-9 secretion and mRNA levels, effects reversed by geranylgeranyl pyrophosphate and mimicked by inhibiting Rho geranylgeranylation or Rho-kinase (ROCK). MMP-9 secretion induced by PDGF/IL-1 was mediated via the ERK, p38 MAPK, and NFkappaB pathways, whereas that induced by TPA was mediated specifically via the ERK pathway. Simvastatin failed to inhibit activation of these signaling pathways. Moreover, simvastatin did not affect MMP-9 mRNA stability. Together these data suggest that simvastatin reduces MMP-9 secretion from human SV-SMC by inhibiting the RhoA/ROCK pathway and decreasing MMP-9 mRNA levels independently of effects on signaling pathways required for MMP-9 gene expression.
Clin Exp Pharmacol Physiol. 2005 Jan-Feb;32(1-2):76-85.
Ledingham JM, Laverty R.
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.
Effect of simvastatin given alone and in combination with valsartan or enalapril on blood pressure and the structure of mesenteric resistance arteries and the basilar artery in the genetically hypertensive rat model.
A research was conducted to investigate the effects of treatment with simvastatin, alone or in combination with valsartan or enalapril, on blood pressure and the structure of mesenteric resistance arteries and the basilar artery in the genetically hypertensive rat model. Simvastatin alone can’t lower the BP at any dose. Simvastatin-enalapril combination and simvastatin-valsartan combination can reduce BP level.
SUMMARY 1. The aims of the present study were to investigate, in the New Zealand genetically hypertensive (GH) rat model, the effects of treatment with simvastatin, alone or in combination with valsartan or enalapril, on blood pressure (BP) and structural remodelling of mesenteric resistance arteries (MRA) and of the basilar artery, an artery that plays a major role in the regulation of cerebral resistance. 2. Genetically hypertensive rats were treated with simvastatin at two dose levels (5 and 10 mg/kg per day) and simvastatin in combination with valsartan or enalapril (also 5 and 10 mg/kg per day) from the age of 7 to 12 weeks. Systolic BP and bodyweight were measured weekly. 3. At the end of the experiment, following fixation by perfusion, MRA and the basilar artery were excised and embedded in Technovit (a glycol methacrylate medium; Heraeus Kulzer, Werheim, Germany). Serial sections were cut and stereological techniques used to determine tunica media width and cross-sectional area (CSA), lumen diameter and the ratio of media width/lumen diameter. 4. Simvastatin monotherapy did not lower BP at either dose. In the high- and low-dose groups, the combination of simvastatin + enalapril lowered BP more than with enalapril alone; this was also true for the simvastatin + valsartan combination in the lower-dose group. 5. The MRA were hypotrophically remodelled by the 10 mg/kg per day dose of simvastatin; the 5 mg/kg per day dose caused hypotrophic remodelling with decreased media/lumen ratio. Valsartan and enalapril caused hypotrophic remodelling together with outward remodelling of the lumen in the 10 mg/kg per day valsartan group and, in all groups, a reduction in the media/lumen ratio, with the greatest effect observed in the high-dose groups. 6. The combination treatments of simvastatin + valsartan and simvastatin + enalapril did not have any consistent extra effect on MRA remodelling. 7. In the basilar artery, high-dose simvastatin had a hypotrophic effect on the media and both doses reduced the media/lumen ratio independently of any change in BP. 8. Simvastatin given in combination with valsartan produced a slight further reduction in medial CSA, media width and ratio. In combination with enalapril, there was little consistent additional effect. 9. Simvastatin monotherapy hypotrophically remodelled the media of the basilar artery in the GH rat model, even in the absence of changes in BP. A similar structural effect may explain, in part, the reduction in stroke seen in patients treated with statins.
Clin Rheumatol. 2005 Mar 2
Tikiz C, Tikiz H, Taneli F, Gumuser G, Tuzun C.
Department of Physical Medicine and Rehabilitation, Faculty of Medicine, University of Celal Bayar, Manisa, Turkey.
Effects of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects: 1-year follow-up study.
An one year follow-up study was conducted to check the efficacy of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects. The treatment using simvastatin showed a short-lived anabolic outcome on bone metabolism. The patient may lose this anabolic outcome by continuation of therapy.
Observational studies suggest that statin use may be associated with lower incidence of fracture. However, there are conflicting data for their effects on bone remodeling parameters and bone mineral density (BMD). In the present study, we aimed to investigate the effects of simvastatin on bone metabolism and BMD in subjects with hypercholesterolemia (>240 mg/dl). For this purpose, 32 postmenopausal osteopenic subjects who were given simvastatin treatment (20 mg/day) and not on osteoporosis treatment were included in the study. During the 1-year follow-up period, the total cholesterol level decreased from 262.1+/-30.9 to 202.2+/-30.1 mg/dl (p<0.0001). At a period as early as the 3rd month, levels of the anabolic markers, e.g., bone-specific alkaline phosphatase (BSAP) and osteocalcin (OCL), were found to be significantly increased (from 120.8+/-56.6 to 149.5+/-57.6 IU/l, p=0.008, and from 20.8+/-12.6 to 34.7+/-18.4 mug/l, p=0.015, respectively) while no significant change was observed in the resorptive marker of serum N-telopeptide of type I collagen (CTX). At the 6th and 12th month, BSAP and OCL were both found to be decreased below the pretreatment values. While a significant reduction was found in BSAP levels (from 120.8+/-56.6 to 55.9+/-18.8 IU/l, p<0.001), no significant change was observed in CTX levels after the 6-month treatment period. Parathyroid hormone showed a gradual profound increase during the follow-up period (from 62.7+/-41.5 to 108.4+/-51.7 pg/ml, p<0.001). No significant change was found in BMD levels at the spine, femoral neck, Ward's triangle, and trochanter at the end of the 1-year follow-up period. In conclusion, simvastatin treatment showed a short-lasting anabolic effect on bone metabolism. However, this effect was lost by prolongation of therapy. The decrease in both anabolic and resorptive markers at the 6th and 12th month suggests that simvastatin affects bone metabolism mostly in favor of inhibition of the bone turnover in a long-term observation period although this inhibitory effect was not reflected in BMD.
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