Effects of fluvastatin, an HMG-CoA reductase inhibitor, on serum levels of interleukin-18 and matrix metalloproteinase-9 in patients with hypercholesterolemia

Leu, Hsin Bang; Chen, Jaw Wen; Wu, Tao Cheng; Ding, Yu An; Lin, Shing Jong; Charng, Min Ji

doi:10.1002/clc.4960280907

Cited by 16 publications

(10 citation statements)

References 30 publications

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“…In particular, these previous studies suggested that the stability of atherosclerotic plaques correlated with the activities of tissue MMPs [16][17][18] and that treatment with hypolipidemic drugs affected the serum level of MMPs. 19,20) To our knowledge, this is the first report showing the ability of MMPIs themselves to reduce serum levels of TG.…”

Section: Discussionmentioning

confidence: 79%

Reducing Effect of Matrix Metalloproteinase Inhibitors on Serum Triacylglycerol in Streptozotocin-Induced Diabetic Rats and Zucker fa/fa Rats

Morikawa¹,

Toyama

Kudo

et al. 2007

Biological & Pharmaceutical Bulletin

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It is known that wound healing involves several matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases at multiple levels of regulation. Retardation of wound healing is one of complications in diabetes mellitus due to increased collagenase activity and reduced granulation tissue in the diabetic wound.1-3) Studies on wound healing in streptozotocin (STZ)-induced diabetic rats suggested the possibility that the reduced breaking wound strength is due to the increased activity of collagenase, which is a member of the MMP family which includes gelatinase and stromelycin. Although it is plausible that inhibition of the accelerated destructive activity of MMPs improves wound healing, the role of MMPs in wound healing has not been fully elucidated yet. To investigate the effects of MMP inhibitors (MMPIs) on wound healing in STZ-induced diabetic rats, we used newly synthesized MMPIs, FYK-1388, FYK-1352 and F61-1008. These compounds have a strong and broad MMP inhibitory activity. Contrary to our anticipation, these MMPIs did not stimulate wound healing in STZ-induced diabetic rats. In the course of our study, unexpected reducing effects on serum triacylglycerol (TG) in STZ-induced diabetic rats and Zucker fa/fa rats were found with these MMPIs. The hypolipidemic effect of these MMPIs is striking and has not been reported until now. We report our results here. MATERIALS AND METHODSMaterials FYK-1388, FYK1352 and F61-1008 were synthesized in Daiichi Fine Chemicals Co., Ltd. The structures and MMP inhibitory activities of these compounds are shown in Table 1. STZ, (4-aminophenyl) mercuric acetate and bovine serum albumin were purchased from Sigma Aldrich Japan (Tokyo, Japan). Pro MMP-3 was obtained from Daiichi Fine Chemicals Co. (Takaoka, Japan); 3168v was from Peptide Institute, Inc. (Osaka, Japan); Brij35 was obtained from Wako Pure Chemicals Ind., Ltd. (Osaka, Japan). IATRO-LQ GLU, IATRO-LQ TG, IATRO-LQ T-CHO(A), IATROTECH NEFA, IATRO-LQ ASAT and IATRO-LQ ALAT were obtained from IATRON (Kyoto, Japan). Rat insulin 125 I assay system was purchased from Amersham (Buckinghansire, England). The other chemiclas were of analytical grade.Experimental Animals Three types of experiments were performed.In Experiment 1 and Experiment 2, male Sprague Dawley rats, aged 5 weeks, were purchased from SLC (Shizuoka, Japan) and acclimatized in a temperature (22Ϯ2°C) and humidity (55Ϯ15%) controlled environments with a 12 h light/dark cycle for at least 6 d before use. They were allowed free access to laboratory chow (MF, Oriental yeast Co., Tokyo, Japan) and water. Animals aged 6 weeks were made diabetic by a single injection of STZ. Two sets of experiments were performed using Sprague Dawley rats. In one set of experiments for the wound healing study (Experiment 1), STZ was intraperitoneally injected at a dose of 65 mg/kg body weigh and animals with a blood glucose concentration greater than 300 mg/ml were assigned to the diabetic group 6 weeks after the administration of STZ. These rats were used for the wound heal...

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Section: Discussionmentioning

confidence: 79%

Reducing Effect of Matrix Metalloproteinase Inhibitors on Serum Triacylglycerol in Streptozotocin-Induced Diabetic Rats and Zucker fa/fa Rats

Morikawa¹,

Toyama

Kudo

et al. 2007

Biological & Pharmaceutical Bulletin

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“…In patients with hypercholesterolemia, MMP-9, IL-18 and endothelial functions were investigated in the presence or absence fluvastatin treatment. Results showed that fluvastatin, but not the placebo, reduced plasma levels of MMP-9, IL-18 and enhanced endothelial function in an independent way from its lipid lowering activity [63]. Rosuvastatin, dosedependently reduced the expression of MMP-7 levels in human monocyte-derived macrophages.…”

Section: Statins and Its Effect On A Major Scavenger Receptor On Macrmentioning

confidence: 97%

Statin Therapy-Evidence Beyond Lipid Lowering Contributing to Plaque Stability

Lorenzo¹,

Feher²,

Martin³

et al. 2006

CMC

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Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol. Several findings from recent research studies indicate that statins have multiple actions that favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions may contribute to the early cardiovascular benefit observed in several outcome trials with statin drugs therapy. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. This review summarise the results of the major outcome trials of statins and non-statins therapy and the possible mechanisms beyond lipid lowering contributing to plaque stability.

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“…29,30 Some investigators report that statins increase the production of IL-18 from human peripheral blood mononuclear cells 31 whereas other content that statins reduce serum IL-18 levels. [32][33][34] The ability of HMG-CoA reductase inhibitors (statins) to modify the inflammatory process continues to attract considerable attention. The effect of statins on cytokines ranges from a reduction in circulating levels of CRP 13,35 to uncertain effects on other cytokines.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory biomarkers CRP, MCP-1, serum amyloid alpha and interleukin-18 in patients with HTN and dyslipidemia: impact of diabetes mellitus on metabolic syndrome and the effect of statin therapy

Rabkin

Langer

et al. 2013

Hypertens Res

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The objective of this study was to determine the relationship of HTN (HTN) and the inflammatory markers C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), amyloid alpha (AA) and interleukin-18 (IL-18) in persons with HTN, considering concomitant diabetes mellitus (DM) or metabolic syndrome (MS). This was a multicenter twelve-week, single-step titration, open-label study of individuals with dyslipidemia, assigned according to their initial risk assessment, to atorvastatin starting doses of 10, 20, 40 or 80 mg. In subjects with HTN (N=677) versus no HTN (N=581), there were significantly (P<0.02) higher levels of CRP, IL-18, MCP-1 and AA but not for IL-18 when combined with DM or MS, and AA or CRP when combined with MS. Systolic blood pressure significantly (P<0.02) correlated with CRP, MCP-1 and AA but not IL-18. The greatest increase in CRP was with HTN plus DM. Statin therapy produced significant dose-dependent reductions in CRP but not with similar changes in other inflammatory markers. In summary, these data suggest a complex relationship between inflammation and HTN with dyslipidemia. Although HTN is associated with an increase in these inflammatory markers, the associated conditions DM or MS lead to different patterns of increases-MCP-1 being the most consistently increased with HTN, the greatest CRP increase was with HTN and DM, and no relationship was found with IL-18 and HTN in the presence of DM or MS. In addition, there are different responses to statins depending on the nature of the inflammatory marker.

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Effects of fluvastatin, an HMG-CoA reductase inhibitor, on serum levels of interleukin-18 and matrix metalloproteinase-9 in patients with hypercholesterolemia

Cited by 16 publications

References 30 publications

Reducing Effect of Matrix Metalloproteinase Inhibitors on Serum Triacylglycerol in Streptozotocin-Induced Diabetic Rats and Zucker fa/fa Rats

Reducing Effect of Matrix Metalloproteinase Inhibitors on Serum Triacylglycerol in Streptozotocin-Induced Diabetic Rats and Zucker fa/fa Rats

Statin Therapy-Evidence Beyond Lipid Lowering Contributing to Plaque Stability

Inflammatory biomarkers CRP, MCP-1, serum amyloid alpha and interleukin-18 in patients with HTN and dyslipidemia: impact of diabetes mellitus on metabolic syndrome and the effect of statin therapy

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