Anti-arteriosclerotic Effects Research Articles

P174 MAGNESIUM IMPROVES METABOLIC PROFILE AND HYPERTENSION

Background and Objective: Magnesium is an essential electrolyte involved in about 600 enzymatic reactions and metabolic processes. Recent data show that nutritive magnesium supplementation decreases interleukin-6 levels and metabolic parameters. Patients and Methods: We conducted a prospective double-blinded, prospective study on magnesium and interleukin-6 and blood pressure values in 27 patients with a metabolic syndrome as compared to 27 controls (all patients beyond 60 years with normal renal function). Patients were supplemented with 400 mg magnesium daily. Measurements of parameters were performed before and after 6 and 12 weeks of treatment. Results: In the magnesium-treated group, interleukin-6 values decreased significantly from 4.94+/-3.30 to 4.53+/-6.89 after 6 weeks to 3.01+/-1.32pg/mL after 12 weeks (mean+/-SD, p < 0.01). In the control group, interleukin-6 was 3.73+/-4.36 before the start of supplementation, 4.87+/-4.35 after 6 weeks, and 4.41+/- 3,15 pg/mL after 12 weeks (n.s.). In the magnesium-treated group, there was also a significant decrease in both systolic and diastolic blood pressure after 12 weeks (systolic: 134.6+/-6.8 to 126.3+/-5.6 mmHG; diastolic: 84.1+/-3.9 to 79.4+/-1.6 mmHg)(mean+/-SD, p< 0.01). HbA1c and lipd profile increased in patients slightly not reaching significane. Vitamin D status also improved significantly in patients after 12 weeks (p< 0.05). For statistics Mann-Whitney U test was used. Conclusions: In patients wit metabolic syndrome, magnesium supplementation significantly decreased interleukin-6 and both systolic and diastolic blood pressure values, vitamin D significantly increased. Metabolic parameters improved. The anti-inflammatory effects of magnesium as well as anti-arteriosclerotic effects are of benefit for patients with a metabolic syndrome at a high risk for cardiovascular diseases and mortality.

The role of endomembrane homeostasis in vascular calcification

Abstract Background Cardiovascular diseases are a leading cause of mortality, with cardiovascular calcification as a prominent predictor and contributor. Microcalcifications in thin fibrous caps of atherosclerotic plaques create biomechanical instability, leading to plaque vulnerability. Recent work indicated that cellular-derived extracellular vesicles (EVs) are pivotal for microcalcification nucleation. EVs can originate from the endolysosomal system, and FYVE-Type Zinc Finger Containing Phosphoinositide Kinase (PIKfyve), a lipid kinase, plays a key role in the endolysosomal maturation. Purpose We hypothesize that alterations in endomembrane homeostasis will modulate EV cargo and, thereby, vascular calcification. Methods and Results In calcified arteries and vascular smooth muscle cells (SMCs), we observed increased PIKfyve expression. Phosphatidylinositol 3-phosphate (PI3P) - the substrate of PIKfyve - was decreased in cellular membranes of calcifying SMCs (-40%) and recovered by Apilimod, a small molecule PIKfyve inhibitor. Apilimod prevented matrix mineralization and collagen network formation in calcifying SMCs (Fig. 1A) accompanied by reduced pro-collagen 1A1 secretion (-90%). Apilimod inhibited tissue non-specific alkaline phosphatase (TNAP) – an early marker of SMC calcification on mRNA, protein and activity level. PIKfyve silencing using siRNA showed similar results. Furthermore, Apilimod caused a dose-dependent increase of EV release assessed by nanoparticle tracking analysis (Fig. 1B). Analysis of the EV cargo demonstrated that Apilimod reduces TNAP protein abundance and activity (-60%) - a characteristic cargo that may determine EV calcification potential. Apilimod-induced EVs exhibited lower mineral content and reduced aggregation potential assessed by osteosense-based flow cytometry and turbidity assays. Next, we performed transcriptome and kinome analyses to discover the underlying mechanism of PIKfye-mediated SMC calcification. These data revealed a link to adipocyte-like differentiation and SMC phenotype specifying pathways. Validation supported increased expression of adipogenic transcription factors (CEBPA, PPARG),genes of the cholesterol and fatty acid metabolism pathways (FABP3, CD36) and enhanced fatty acid (C12) uptake (Fig. 1A) by Apilimod; while SMC-specific markers (ACTA2, SM22) and key SMC transcription factors (GATA6, MYOCD) were downregulated. Finally, in Ldlr-deficient mice fed a high-fat, high-cholesterol diet for 15 weeks, Apilimod application for 5 weeks increased PI3P levels (1.6-fold) and decreased vascular calcification (Fig. 1C), but did not alter plaque size or collagen content in atherosclerotic plaques. Conclusion Disrupting endolysosomal maturation with Apilimod promotes the release of EVs with reduced calcification potential and induces a phenotypic adaption towards adipocyte-like SMCs, causing reduced SMC calcification. Anti-arteriosclerotic effects of Apilimod in vivo remain to be further investigated.Figure

4-Methoxyphenyl (E)-3-(Furan-3-yl) Acrylate Inhibits Vascular Smooth Muscle Cell Proliferation.

The Cordyceps extract exhibits antiproliferative potential in vascular smooth muscle cells (SMCs) through the mitogen-activated protein kinase signaling pathway. In this study, we aimed to identify the active compounds in the Cordyceps extract and analyze their role in remodeling the arterial wall. On investigation, we discovered the following active compound: 4-methoxyphenyl (E)-3-(furan-3-yl) acrylate and synthesized it. We performed antiproliferation and antimigration assays in addition to an in vivo vessel wall remodeling experiment. Investigation of the mechanism adopted by the active compound to remodel the vessel was performed. The newly synthesized compound inhibited the proliferation and migration of SMCs. Treatment with the synthesized compound reduced neointima formation in the balloon-injured Sprague-Dawley rat model. In addition, this compound inhibited the activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 in type I collagen-activated SMCs. Moreover, this compound suppressed the expression of cycloxygenase-2 (COX-2) in SMCs. Therefore, this compound can exert potential antiarteriosclerotic effects by modulating vessel wall remodeling. In conclusion, the newly synthesized 4-methoxyphenyl (E)-3-(furan-3-yl) acrylate might be an alternative therapeutic intervention for the treatment of atherosclerosis.

Anti-atherosclerotic effects of an improved apolipoprotein A-I mimetic peptide

BackgroundApolipoprotein (Apo)A-I is a major protein component of high-density lipoprotein (HDL) that causes cholesterol efflux from peripheral cells through ATP-binding cassette transporter A1 (ABCA1) and the generation of HDL. Furthermore, it has a possible protective function against atherosclerotic cardiovascular disease (ASCVD). We previously developed a novel ApoA-I mimetic peptide without phospholipids (Fukuoka University ApoA-I Mimetic Peptide, FAMP). According to our previous studies, FAMP had an anti-arteriosclerotic effect. Since the required dose and reaction time of conventional FAMP were relatively large and short, respectively, we newly developed an improved FAMP (i-FAMP). Methods and resultsWe synthesized four candidate i-FAMPs, i-FAMP-D1, -D2, -D3 and -D4, and examined which i-FAMP has greater cholesterol efflux capacity than FAMP in A172 human glioblastoma cells transiently transfected with human ABCA1 cDNA. Only i-FAMP-D1 showed significantly greater cholesterol efflux capacity than conventional FAMP. i-FAMP-D1 formed stronger α-helical conformations than FAMP as assessed by circular dichroism spectra. Thus, we selected i-FAMP-D1 for further experiments. i-FAMP-D1 had a greater atheroprotective effect than FAMP in ApoE knockout mice. In addition, i-FAMP-D1 activated cholesterol efflux from macrophage to HDL more strongly than FAMP and increased cholesterol excretion from liver to feces. ConclusionThese results suggest that i-FAMP-D1 has a stronger anti-atherosclerotic effect than conventional FAMP.

Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity

It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression.

Influence of dietary intake of fish oil, magnesium, and zinc on metabolic parameters among individuals tested for diabetes

ObjectiveThe aim of this study was to assess the significance and degree of correlation between the intake of fish oil, magnesium (Mg), and zinc (Zn) and metabolic parameters. MethodsCorrelation coefficients among nutrient intake and physical and laboratory parameters were determined using Spearman's rho (ρ) test or a multiple regression model among Japanese individuals (male:female, 37:66; median age, 55 y) who completed a semiquantitative food questionnaire and underwent testing for diabetes. Individuals with diabetes were excluded. ResultsSpearman's test revealed several weak but significant correlations between intake of fish oil including ω-3 polyunsaturated fatty acids (PUFAs) and various metabolic parameters. The test showed that Zn intake in women significantly correlated with reduced systolic blood pressure (SBP), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GPT), and homeostasis model assessment–insulin resistance (HOMA-IR). Multivariate analysis revealed that intake of fish oil, eicosapentaenoic acid (EPA), and Zn was significantly associated with increased serum levels of high-density lipoprotein cholesterol (HDL-C; fish oil versus HDL-C, P = 0.0438; 95% confidence interval [CI], 0.0055–0.3724; EPA versus HDL-C, P = 0.0439; 95% CI, 0.0053–0.3724; Zn versus HDL-C, P = 0.0041; 95% CI, 0.0890–0.4609). Multivariate analysis revealed that ω-3 PUFAs were associated with decreased serum ALT levels (P = 0.0240; 95% CI, −5.000 to −0.0367) and that Zn correlated with SBP (P = 0.0239; 95% CI, −0.5149 to −0.0377) in women. ConclusionIntake of fish oil, Mg, and Zn was associated with some metabolic parameters. Abundant intake of fish oil including ω-3 PUFAs and Zn can exert antiarteriosclerotic effects through increasing serum levels of HDL-C. ω-3 PUFAs can reduce liver inflammation and Zn can reduce SBP in women.

Effects of Telmisartan on Inflammatory Cytokines and Coronary Plaque Component as Assessed on Integrated Backscatter Intravascular Ultrasound in Hypertensive Patients

Telmisartan has unique pleiotropic effects in addition to renin-angiotensin system (RAS)-inhibition effects. The aim of this study was to evaluate the effects of telmisartan on the coronary plaque component and local inflammatory cytokines. A total of 50 patients with hypertension were randomized to 2 groups: the telmisartan group (additional treatment with telmisartan 80mg/day, n=25) or the control group (additional treatment with other anti-hypertensive drugs except RAS blockers, n=25) for 6 months. Tissue characteristics of target coronary plaque were analyzed using integrated backscatter intravascular ultrasound (IB-IVUS) before and after treatment. Plasma levels of inflammatory cytokines sampled in the coronary sinus (CS) and peripheral vein were also measured. Significant increases in fibrous volume (51.2±10.4 to 58.3±7.7%, P=0.03) and reductions in lipid volume (38.4±12.4 to 32.8±9.7%, P=0.03) were observed on IB in the telmisartan group, while there were no significant changes in the plaque component in the control group. CS levels of inflammatory cytokines (matrix metalloproteinase [MMP]3, tumor necrosis factor-α, high-sensitivity C-reactive protein and MMP9) were lower after than before treatment in the only telmisartan group (7.7±6.1 to 5.5±4.9ng/ml, 3.1±1.9 to 2.3±2.0pg/ml, 5.6±6.0 to 2.2±2.4mg/L, 36.1±39.3 to 19.9±27.5ng/ml, P=0.02, P=0.03, P=0.04, P=0.07, respectively). Decreased local inflammatory response and plaque stabilization on IB imaging were observed after 6 months of telmisartan treatment. These findings might be associated with local anti-inflammatory and anti-arteriosclerotic effects of telmisartan.

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Effects of six-week cardiac rehabilitation and exercise on adiponectin in patients with acute coronary syndrome

Increased adiponectin is a result of an anti-arteriosclerotic effect and is related to the prevention of arteriosclerosis. However, it is uncertain whether cardiac rehabilitation and exercise (CRE) increase adiponectin in patients after acute coronary syndrome (ACS). To assess the effects of CRE intervention on adiponectin in patients after ACS. Forty four patients participated in a cardiac rehabilitation programme after receiving percutaneous coronary intervention. The participants were divided into either an intervention (CRE) or a control (CON) group. Assessments were made at baseline and six weeks after the intervention for adiponectin, interleukin-6 (IL-6), tumour necrosis factor-a (TNF-a); high sensitivity C-reactive protein (hs-CRP), waist-to-hip ratio (WHR), and exercise duration. After six weeks of exercise training, adiponectin significantly increased in both CRE and CON (p < 0.001 and p = 0.009, respectively). Adiponectin showed a significantly greater increase in CRE than in CON (p = 0.032). Significant differences were not observed in IL-6, TNF-a, and hs-CRP between the groups. However, VO(2max) and exercise duration significantly increased in CRE (p < 0.001). Significant increases in VO(2max) and exercise duration were also observed in CRE but not in CON (p < 0.001). WHR significantly decreased in CRE, with no significant change in CON (p < 0.05). The difference in adiponectin between the groups showed a significantly inverse relationship with the difference in WHR (R² = -0.376, p = 0.034). Adiponectin and cardiopulmonary fitness were significantly increased in CRE after six weeks of intervention. Although reductions in inflammatory markers were not observed, a significant inverse correlation was observed between the changes in adiponectin and WHR in CRE. Therefore, six weeks of short-term CRE intervention had a significant anti-inflammatory effect.

Abstract TP181: Serum Eiocosapentaenoic Acids Is Protective Against White Matter Lesions

[Introduction] White matter hyperintensities (WMH) are considered manifestation of arteriosclerotic small vessel disease and WMH burden increases risk of ischemic stroke and cognitive decline. There are only a few evidences concerning the relationship between polyunsaturated fatty acids (PUFA) and WMH. The present study was designed to elucidate the association between WMH and PUFA profile including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) in patients with Alzheimer’s disease (AD). [Methods] The present study was based on 119 patients who were diagnosed as having a probable AD according to the NINCDS-ADRDA criteria. Their mean age was 78.3 years old. All subjects underwent neuropsychological evaluation including mini mental state exam (MMSE) and 1.5-Tesla MRI. Fasting blood samples were also collected for the PUFA measurements. We measured the ratio of serum EPA, DHA and AA concentration to the total PUFA concentration. The WMH were evaluated on T2-weight images and classified into periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH). The severity of WMH was graded 5 categories. We investigated the relationship between WMH and PUFA profiles. [Results] The EPA ratio correlated negatively with both PVH (rs=-0.2036, p=0.0264) and DWMH grade (rs=-0.3155, p=0.0005). It remained still significant after adjustment for age, sex, statins use, antithrombotics use, mean blood pressure and presence of hypertension (standardized partial regression coefficient(β)=-0.2516, p=0.0122 for PVH, β=-0.3598, p=0.0001 for DWMH). Neither DHA nor AA ratio correlated with DWMH or PVH grade. The EPA ratio but not DHA or AA ratio correlated positively with total MMSE score (rs=0.2310, p=0.0115). [Conclusions] Our data revealed that the serum EPA was protective against WMH as well as cognitive decline in AD patients. Pathophysiology underlying WMH is complex and the possible mechanisms involved in the pathogenesis of WMH encompass incomplete brain ischemia, increased permeability of blood-brain barrier, and inflammation responses. The relationship between serum EPA and WMH can be partly explained by those anti-ischemic and anti-arteriosclerotic effects of EPA.

Relationship between serum cystatin C and serum adiponectin level in type 2 diabetic patients

To investigate the relationship between serum levels of cystatin C and adiponectin in patients with type 2 diabetes. We examined serum cystatin C and adiponectin levels in 234 patients with type 2 diabetes who visited our hospital. The serum level of cystatin C was positively correlated with age (P < 0.001), duration of diabetes (P = 0.013), serum creatinine (P < 0.001), uric acid (P < 0.001), and adiponectin (p = 0.001), while it was inversely correlated with estimated glomerular filtration rate (P < 0.001). Serum adiponectin was significantly higher in patients with high serum cystatin C levels than in those with normal cystatin C levels (8.3 ± 4.7 and 6.2 ± 3.2 μg/mL, respectively; P < 0.001). Adiponectin was also significantly higher in male patients with high cystatin C levels, but not in females. In multiple regression analysis, serum adiponectin was also independently and significantly correlated to age, diastolic blood pressure, high-density lipoprotein cholesterol, triglyceride and serum cystatin C. Serum adiponectin level was correlated with serum cystatin C level on simple and multiple regression analyses in patients with type 2 diabetes. Although circulating adiponectin is increased in advanced kidney disease, it might be biologically inactive due to binding to cystatin C and thus not display an anti-arteriosclerotic effect.

Abstract 9345: Effects of Telmisartan on Inflammatory Cytokines and Coronary Plaque Component Assessed by Integrated Backscatter Intravascular Ultrasound in Hypertensive Patients

Backgrounds: Recently, assessment of the plaque composition has become possible using an integrated backscatter intravascular ultrasound (IB-IVUS). The pleiotropic effect of telmisartan has been focused, however, effects of telmisartan on coronary plaque component and inflammatory cytokines are not known. Methods: A total of 31 patients with hypertension were randomized to two groups: telmisartan group (treatment with telmisartan [80mg/day, n=16]) or control group (other antihypertensive drugs except renin-angiotensin system blocker, n=15) for six months. The tissue characteristics of target coronary plaque in each patient were analyzed using IB-IVUS before and after treatment. We also measured plasma levels of inflammatory cytokines sampled in coronary sinus (CS) and peripheral vein (PV). Results: Mean lumen area significantly increased (7.9±2.2 to 8.5±2.6 mm2, p&lt;0.05) and plaque volume significantly decreased (21.1±6.0 to 19.4±6.2 mm3, p&lt;0.01) after treatment with telmisartan. Additionally, significant increases of fibrous volume (47.3±9.3 to 63.1±4.1%, p&lt;0.05) and reduction of lipid volume (37.5±15.4 to 24.8±8.6%, p&lt;0.05) were observed on IB image analyses in the telmisartan group, while there were no significant changes in plaque component in the control group. The CS-levels of MMP3 and hsCRP were smaller after than before treatment with telmisartan (7.6±6.1 to 5.5±4.9 ng/ml, 5.6±6.0 to 2.2±2.4 mg/l, p&lt;0.05, respectively), however, there were no significant differences in cytokine levels between pre- and post-treatment with other antihypertensive drugs. In the PV-levels of those cytokines, there were no significant differences between pre- and post-treatment in the two groups. Conclusions: Decreased local inflammatory response and plaque stabilization on IB image analyses were observed after six months of telmisartan treatment. These findings might be associated with local anti-inflammatory and antiarteriosclerotic effects of telmisartan.

Leberschutz, Verdauungsbeschwerden, Lipidsenkung – Multitalent Artischocke

The artichoke has been used for a long time in kitchen and pharmacy. In the seventies of the 20 th century the current research concerning the pharmacological effects has begun. Choleretic, hepatoprotective, anticholestatic, lipid-lowering and anti arteriosclerotic effects are proven. Commission E recommends the artichoke in the case of dyspeptic complaints. The paper gives an overview of the current state of research concerning the use of artichoke extracts.

Clinical Summaries

Clinical Summaries

Effect of pioglitazone on various parameters of insulin resistance including lipoprotein subclass according to particle size by a gel-permeation high-performance liquid chromatography in newly diagnosed patients with type 2 diabetes

Pioglitazone is an insulin-sensitizing agent that has been reported to have anti-arteriosclerotic effects. The aim of this study was to obtain a better understanding of the mechanism involved in the insulin sensitizing effect of pioglitazone. A total of 50 newly diagnosed patients with type 2 diabetes were enrolled in this study and divided into two groups, 25 of who were treated with 15 mg/day pioglitazone and 25 with 500 mg/day metformin for 12 weeks. Changes in various parameters of insulin resistance including lipoprotein subclass according to particle size determined by high performance liquid chromatography, as well as glucose metabolism, were monitored to determine the relationship between lipoprotein subclass and other insulin resistance parameters. Both pioglitazone and metformin treatment were associated with significant reductions in hyperglycemia, HOMA-IR and HbA1c levels. Pioglitazone treatment, but not metformin treatment resulted in significant reductions in serum large very low-density lipoprotein (VLDL: 44.5-64.0 nm) and increases in serum adiponectin levels (both <0.001). In the pioglitazone group, the change in large VLDL levels correlated positively with changes in HbA1c (r=0.468, P=0.0174), HOMA-IR (r=0.593, P=0.0014), very small LDL (r=0.714, P<0.0001) and net electronegative charged modified-LDL (r=0.412, P=0.0399), and inversely with changes in adiponectin level (r=-0.526, P=0.0061). The results in this study suggest that the hypoglycemic effect of pioglitazone is achieved mainly through improvement of hepatic insulin resistance, and that pioglitazone may have an antiatherosclerotic effect by decreasing serum atherogenic modified-LDL and by increasing adiponectin.

Modification of cardiometabolic pathways as a potentially new therapeutic approach for the ageing and the failing heart?

Recent results show that caloric restriction (CR) improves existing disturbances in cardiac function independent from anti-arteriosclerotic effects. Signalling from adipose tissue to other organs via adipokine-mediated activation of AMP-activated protein kinase (AMPK) contributes to the protection by CR. Therefore, we investigated whether age and nutritional status influence the expressional pattern in cardiac and adipose tissue. Methods: We obtained samples from the right atrium (RA), epicardial and subcutaneous adipose tissue together with a blood sample from male young/old (54,5±4,1 years/77,1±2,9 years) and normosome/obese (BMI 24,0±1,1/BMI 33,8±4,3) patients undergoing cardiac surgery. Mitochondrial respiratory function, the expression of apoptotic and load-associated markers were measured by Real-time PCR together with the expression and plasma release of selected adipokines. Results: Mitochondrial function is depressed in older patients with a further deterioration with advanced obesity. Furthermore, the expression of proapoptotic proteins (Bcl-xS, Bax) or load-induced markers (BNP, beta MHC) are enhanced in old and in young obese patients. Protective adipokines such as adiponectin are reduced in both adipose tissues and in plasma samples in old and in young obese patients and this results in reduced AMPK. Conclusion: These changes in myocardial and adipose tissue gene expression support the occurrence of early alteration associated with obesity even in younger patients. Cardiometabolic pathways activated during CR may yield targets for pharmacological mimetics of selected components within the spectrum of CR actions and may thus yield a promising strategy to improve cardiac function in obese patients.

Nitric Oxide and Endoplasmic Reticulum Stress

Nitric oxide (NO) is a multifunctional biomolecule involved in a variety of physiological and pathological processes, including regulation of blood vessel dilatation and anti-arteriosclerotic effects. However, a large amount of NO is toxic to the host and causes several diseases such as apoptosis, septic shock, and diabetes mellitus. Inducible-form NO synthase is induced in inflammatory diseases, including insulitis and arteriosclerosis. Endoplasmic reticulum (ER) stress pathway was first identified as a cellular response pathway induced by the accumulation of unfolded proteins in ER to preserve ER functions. Later it was found that ER stress pathway is also activated by various cellular stresses to protect cells, but when stresses are severe, apoptosis is induced to remove damaged cells. It is reported that NO and reactive oxygen species disturb ER functions, then ER stress-mediated apoptosis pathway is activated. CHOP/GADD153, which belongs to C/EBP transcription factor family, is induced in this process and mediates apoptosis. ER stress pathway induced by NO can be involved in the pathogenesis of various vascular diseases.

Effect of pioglitazone on arteriosclerosis in comparison with that of glibenclamide

Background: Pioglitazone is an insulin-sensitizing agent that has been reported to have anti-arteriosclerotic effects. Objective: To investigate the anti-arteriosclerotic effects of pioglitazone in patients with diabetes mellitus using pulse wave velocity (PWV) as an index of efficacy. Methods: Twenty-seven patients with type 2 diabetes mellitus were randomly assigned to two groups, and pioglitazone ( n = 13) or glibenclamide ( n = 14) was administered for 6 months. The TG, TC, LDL-C, and HDL-C, FPG, HbA1c, IRI levels, HOMA-IR, and ba-PWV data were examined before and after administration of each agent. Results: FPG and HbA1c were significantly improved in both the groups after treatment, but IRI, HOMA-IR and were improved only in the PIO group. The percent change of ba-PWV from the baseline after treatment in the PIO group improved significantly than that in the GC group (−6.3 ± 5.6% versus 0.8 ± 5.7%). Conclusions: The findings in this study suggested that pioglitazone has anti-arteriosclerotic effects. We concluded that drugs for the treatment of diabetes mellitus should be selected taking into consideration such endpoints as blood sugar control, and also the risk of complications such as cardiovascular events in the future.

A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane

Adiponectin, which is produced by adipose tissue, is thought to play an important role in inflammation. On the other hand, adiposity, or the hypertrophy of adipose tissue, has been reported to increase oxidative stress. Accordingly, the possibility exists that adiponectin, as well as leptin, influences oxidative stress, resulting in a proinflammatory state. However, the relationship between adiponectin and oxidative stress is unclear. We examined 259 Japanese Americans living in Hawaii who were diagnosed as having normal glucose tolerance (NGT), impaired glucose tolerance, or diabetes by a 75-g oral glucose tolerance test. First, we measured their serum adiponectin, leptin, and high-sensitivity C-reactive protein levels as markers of inflammation, and urinary 8-iso-protaglandin F 2 α (isoprostane) as a relevant marker of oxidative stress. We investigated the relationship between adiponectin or leptin and isoprostane among these subjects. In the diabetic subjects, the adiponectin and leptin levels were significantly lower and higher, respectively, than among the NGT subjects. Urinary isoprostane levels tended to decrease significantly after a rise in adiponectin levels ( P = .014) among the NGT subjects. Next, we investigated the association between the 2 adipocytokines and isoprostane by regression models. Adiponectin was negatively but significantly associated with urinary isoprostane levels adjusted for age, gender, and smoking status, whereas leptin was positively and significantly correlated with urinary isoprostane levels ( P = .014 and .004, respectively). With respect to adiponectin, this association was attenuated but still significant when further adjustments were made for waist-to-hip ratio, body mass index, percent body fat, C-reactive protein levels, glucose tolerance status, or homeostasis model assessment. In conclusion, this study suggests that adiponectin and leptin might be associated with oxidative stress levels. These results also suggest the possibility that adiponectin might modulate oxidative stress, leading to antidiabetic and anti-arteriosclerotic effects.

Effects of Fluvastatin on Plasma Levels of Low-Density Lipoprotein Subfractions, Oxidized Low-Density Lipoprotein, and Soluble Adhesion Molecules: A Twenty-Four–Week, Open-Label, Dose-Increasing Study

Background: Statins not only lower low-density lipoprotein (LDL) levels, but also have several antiarteriosclerotic effects (eg, decreasing arterial inflammation and arterial smooth muscle cell proliferation, as well as antioxidant effects). The relationship between the dose of statin and its effects on plasma LDL levels and other arteriosclerosis-related effects remains to be clarified. Objective: We investigated the effect of a statin, fluvastatin, on plasma levels of lipoprotein subfractions, oxidized LDL (Ox-LDL), Ox-LDL immunoglobulin G (IgG), soluble adhesion molecules, reverse cholesterol transport (ie, transport of esterified high-density lipoprotein cholesterol [HDL-C] to triglyceride [TG]-rich lipoproteins by cholesteryl ester transfer protein [CETP] and reduction of plasma HDL-C levels), and on the intima-medial thickness (IMT) of the common carotid arteries. Methods: Patients with nonfamilial type 2 hyperlipoproteinemia were eligible for this open-label, dose-increasing study. Fluvastatin 20 mg/d was administered for the first 12 weeks, and the daily dose was increased to 40 mg for the subsequent 12 weeks. Patients were examined at baseline and after 12 and 24 weeks of treatment. Plasma lipoprotein subfractions were determined using sequential ultracentrifugation at 100,000 g. The plasma levels of Ox-LDL, Ox-LDL-IgG, CETP, and soluble adhesion molecules were measured using sandwich enzyme-linked immunosorbent assay. The maximum IMT of the common carotid arteries was measured using sonography. Results: The plasma levels of LDL cholesterol (LDL-C) and apolipoprotein (apo) B were reduced by 25% and 17%, respectively ( P<0.001 for both), after 12 weeks of treatment with fluvastatin 20 mg/d; no further significant reductions in LDL were observed after increasing the daily dose to 40 mg. Fluvastatin 20 mg/d for 12 weeks decreased plasma levels of intermediate-density lipoprotein cholesterol, LDL-I-C, LDL-II-C, and LDL-III-C by 25% ( P<0.01), 30% ( P<0.001), 23% ( P<0.01), and 20% ( P = 0.02), respectively. No further significant reductions in these levels were observed after increasing the daily dose to 40 mg. The plasma levels of Ox-LDL decreased in a similar fashion to the plasma levels of LDL-C ( P<0.001). However, plasma levels of Ox-LDL-IgG and soluble P-selectin did not decrease after 12 weeks of fluvastatin 20 mg/d, but did decrease significantly (both 22%) after the next 12 weeks of treatment with fluvastatin 40 mg/d ( P<0.05). Plasma levels of intercellular adhesion molecule 1and vascular cell adhesion molecule 1 and CETP mass were not altered by fluvastatin treatment. Significant changes in maximum IMT of the common carotid arteries were not seen throughout 24 weeks of fluvastatin treatment. Conclusions: In this patient population, fluvastatin 20 mg/d was sufficient to significantly reduce plasma levels of LDL, the 3 LDL subfractions, and Ox-LDL, but was not sufficient to reduce plasma levels of Ox-LDL-IgG and soluble P-selectin. It is important to check not only plasma lipoprotein levels but also other factors relating to arteriosclerosis during treatment with statins for the prevention and treatment of arteriosclerosis.