Metabolic Syndrome Atherosclerosis Research Articles

Urinary Adiponectin as a Predictor of Carotid Atherosclerosis in Metabolic Syndrome in Type 2 Diabetics

Urinary Adiponectin as a Predictor of Carotid Atherosclerosis in Metabolic Syndrome in Type 2 Diabetics

Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL).

Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.

Determinants of Adult Obesity in the Working Area of the Simpang Tiga Community Health Center Pekanbaru City

Obese is a overweight as a result of plutonium body fat excessive. Based on the data from health department the city of pekanbaru 2016 the proportion of the incident obesity was highest for puskesmas simpang three of which was 2.1 % per 19.029 population. Based on preliminary survey, than 20 respondents there were as many as five people ( 25 % ) suffering from obesity. Obesity have an impact on the emergence of various degenerative diseases among others, metabolic syndrome atherosclerosis, of cardiovascular diseases, diabetes, gallstones, disturbance of function pulmonic, hypertension and dislipidemia. Research objectives know determinan scene obesity in community in the work area of puskesmas simpang 3 the city of pekanbaru 2017. The research was quantitative analytic with a kind of design study cross section analitik. Variabel dependent obesity and independent variable was education, knowledge, sex, offspring, physical activity and the habit of eating. The study was done in the work area of puskesmas simpang 3 the city of pekanbaru, data collection was held in december 2017 - january 2018. Population to research it was a whole people living and settled in the work area of puskesmas simpang 3 the city of pekanbaru 2018 as many as 19.029 lives and sample were 155 responden. teknik the sample collection of sampling quota. Data analyswas univariat, bivariat and multivariate. The results of the study showed that well educated low (SMP), the offspring of obesity and the habit of eating little influence to events obesity. It was suggested that puskesmas simpang 3 the city of pekanbaru harder socialize a healthy lifestyle like how diet good to avoid from obesity especially the targets to the education low and have the acts of offspring obesity.

Assessment of Arterial Stiffness in Metabolic Syndrome Related to Insulin Resistance in Apparently Healthy Men.

Assessment of subclinical atherosclerosis in metabolic syndrome is one of the global health targets' priorities. This study aimed to evaluate the subclinical atherosclerosis in metabolic syndrome related to insulin resistance in healthy and physically active men. A consecutive group of 68 healthy men, 30-55 years of age, was studied. Anthropometric parameters, proinflammatory factors, and insulin level were measured, and pulse wave analysis (PWA) was performed by applanation tonometry and then processed with dedicated software (SphygmoCor®). The metabolic syndrome was defined according to International Diabetes Federation (IDF) and metabolic health as ≤1 component of metabolic syndrome according to the Joint Interim Statement criteria. The odds ratio of insulin resistance for metabolic syndrome was 5.16 (95% confidence interval: 1.44-18.5), P = 0.008. In PWA, metabolically healthy subjects had lower aortic systolic and diastolic, and cardiac end-systolic pressures (103.5 ± 9.9 vs. 108.8 ± 11.0), P = 0.03, (76.2 ± 8.8 vs. 80.6 ± 7.8), P = 0.04, and (96.5 ± 9.2 vs. 101 ± 10.1), P = 0.05, respectively. Furthermore, metabolic syndrome was accompanied by higher ejection duration% (38.8 ± 3.5 vs. 36.9 ± 2.8), P = 0.04, and lower subendocardial viability ratio (SEVR) (139.8 ± 17.7 vs. 150.9 ± 17.6), P = 0.05. Insulin resistance was associated with higher cardiac end-systolic pressure (103.0 ± 6.9 vs. 96.7 ± 10.4), P = 0.015. Metabolic risk factors had incremental correlations with central arterial pressures and cardiac end-systolic pressure. Furthermore, the composite of metabolic syndrome components imposed additional load on cardiac muscle by higher cardiac ejection duration and impairment in perfusion with lower Buckberg SEVR. Likewise, insulin resistance could be an early marker of arterial stiffness in healthy and active young to middle-age men.

The Role of Triacylglycerol in the Oxidizability of Low Density Lipoproteins and High Density Lipoproteins: Possible Contributions to Atherosclerosis in Metabolic Syndrome

Objective: Metabolic Syndrome (MetS) is a cluster of Cardio-Vascular Disease (CDV) risk factors including visceral obesity, hyperglycemia, hypertension, low HDL cholesterol, hypertriglyceridemia and increased oxidative stress. Pyrene-lipid derivatives selectively incorporated into the hydrophobic core and surrounding amphipathic envelope of LDLs and HDLs are useful markers of the oxidizability of these lipoprotein regions. We performed an observational study aimed at investigating the effect of lipid composition, in particular triacylglycerol (TAG) levels, on the oxidizability of the core and the envelope of LDLs and HDLs in MetS.Methods: We induced changes in the chemical composition of lipoprotein in vivo by placing on a hypocaloric balanced diet fifteen overweight and moderately obese men (BMI: 25-35 kg/mq) with MetS until they lost at least 5% of their initial weight. The core and the surface of LDLs and HDLs were labeled with selective pyrenic probes. Susceptibility to 2,2'-azobis-2-methyl-propanimidamide-dihydrochloride-induced peroxidation was measured following kinetically the decrease of fluorescence of these probes. The length of the lag phase (lag-time) of peroxidation kinetic were calculated and used as indices of lipoprotein oxidizability. In addition, we measured paraoxonase activity and plasma oxidative status.Results: After weight loss, together with a reduction of triglyceridemia and the improvement of the other CDV risk factors associated with MetS, we observed a massive transfer of TAG from HDLs toward LDLs. In the LDLs core, the increased TAG concentration halved the resistance to peroxidation, while in the HDLs core the reduction of this parameter doubled the value of lag-time. In the lipoprotein hydrophobic cores, the duration of lag-time correlated directly with ratio between cholesteryl esters and TAG. No significant changes were found in paraoxonase activity and plasma oxidative status.Conclusions: Less oxidizable HDLs, but also more oxidizable LDLs seem to accompany the improvement of different metabolic factors induced by weight loss in obese men with MetS.

HDL-C, ApoA1 and VLDL-TG as biomarkers for the carotid plaque presence in patients with metabolic syndrome

AimHypercholesterolemia and hyper LDL-C are associated with the atherosclerosis (AS). The current study was performed to evaluate the implication of the others lipoproteins (HDL, LDL, VLDL) and apolipoproteins (ApoA1, ApoB100) with subclinical atherosclerosis (carotid plaque) in patients with metabolic syndrome (MetS) free from cardiovascular disease (CVD). MethodsProspective transversal study was conducted in patients with MetS free from cardiovascular disease (CVD). The lipids, lipoproteins and apolipoproteins were measured. The lipoproteins (HDL, LDL, VLDL) were obtained by the precipitation method. The carotid plaque (CP) was evaluated by ultrasonography, method for assessing AS. Logistic regression and analysis tree were used to look for the association and the incrimination of the lipoproteins with the presence of CP. ResultsThe CP incidence was 60% among the participants, 34.29% on the right and the left plaque against 25.71% for only one plaque. The HDL-C was the only lipoprotein associated with the CP after adjustment of the age, the sex and BMI (OR: 0.007 P: 0.046) with the logistic regression analysis, HDL-C (<0.35 g/l), ApoA1 (<1.43 g/l) and VLDL-TG (>0.656 g/l) are implicated in the presence of CP with the analysis tree analysis. ConclusionLower level of HDL-C is associated with CP, HDL-C, ApoA1, and high level VLDL-TG but not total cholesterol, and LDL-Care useful parameters in the assessment of initial atherosclerosis in metabolic syndrome.

Gender-Specific Association of Desacylated Ghrelin with Subclinical Atherosclerosis in the Metabolic Syndrome

Ghrelin, a gastric hormone with pleiotropic effects modulates vascular function and may influence atherosclerosis. Plasma ghrelin is reduced in the metabolic syndrome (MS), which is also characterized by early atherosclerosis. Ghrelin circulates in acylated (AG) and desacylated (DAG) forms. Their relative impact and that of gender on subclinical atherosclerosis in MS is unknown. To investigate potential associations of total, AG and DAG with carotid atherosclerosis and with gender in the MS. Plasma total ghrelin, AG, DAG and carotid artery IMT (cIMT) were measured in 46 MS patients (NCEP-ATP III criteria, 22M/24F). Compared with males, females had higher (p <0.05) total and DAG. In the association analysis, age and plasma glucose were positively (p <0.05) correlated with cIMT in all MS patients. The positive (p <0.05) association between cIMT and age was also confirmed in males, while that between cIMT and glucose was significant in women. In contrast, neither total ghrelin nor AG and DAG were associated with cIMT in all MS patients nor in the male subgroup. In females, a negative (p <0.05) association between carotid artery IMT, DAG and glucose was detected, but not between cIMT, total ghrelin and AG. In multivariate modeling, DAG remained negatively (p <0.05) associated with cIMT after adjusting for plasma glucose and cardiovascular risk factors. These data indicate a negative independent association between DAG and cIMT in middle-aged women with the MS and suggest a gender-specific modulatory function of DAG in the development of atherosclerosis.

Abstract 11839: Obesity Related Heart Rate Changes among Young Hispanic Women with Metabolic Syndrome

Introduction: Visceral adiposity and metabolic syndrome have an earlier onset among Hispanic women due to genetic susceptibility. This study aimed to determine the association between changes in BMI, body weight and heart rate (HR) among Hispanic women aged 31-49years who met the ATP III criteria for metabolic syndrome and Obesity. Hypotheses: 1. There is a positive relationship between changes in BMI and Basal Heart rate 2. Patients with higher BMI will have a higher heart rate. Methods: In this retrospective study conducted in a community clinic, patient records meeting eligibility criteria were screened for three complete readings of anthropometric measurements and Vital signs. The readings taken when the patients had elevated temperature, respiratory rate, Blood pressure or when they were on Beta blockers were excluded. Final sample consisted of 61 records. Results: The sample BMI varied from 25 to 55 (Mean 34; SD 6) and the body weight ranged from 118lbs to 282lbs (Mean 188lbs; SD 35). The BMI change was between -4 to +4 (mean 1.15; SD 1.6), body weight change was from-30lbs to 22lbs (Mean 6.08 and SD 8.7) and the HR varied from -12 to 25 (mean 4.76; SD 8.38) Over 34 months. First hypothesis was accepted because Spearman Rho showed a significant positive correlation (r.298 p&lt;.05) between changes in BMI and HR and between changes in body weight and HR (r.304 p&lt;.05). A BMI change of one point raised the heart rate by 2beats/minute or 120beats/ hour accounting for 2,880 times/day. There was a no significant correlation between BMI and HR at all three data points leading reject the second hypothesis and conclude that the patients with highest BMI may not have the highest HR. Conclusions: The data showed that patients with metabolic syndrome and obesity suffer significant sympathetic stimulation raising basal HR, even when their blood pressure is controlled causing deleterious effect on already compromised heart with hypertension and atherosclerosis in metabolic syndrome. Patients with highest BMI may not have the highest HR due to failure to evoke an adequate sympathetic response and autonomic neuropathy signaling progressive chronic illnesses.

Reversal of Early Atherosclerosis in Metabolic Syndrome by Yoga – A Randomized Controlled Trial

Metabolic syndrome (MetS) is a strong risk factor for Coronary Heart Disease (CHD) and type II Diabetes mellitus (DM). The aim of the present study was to determine whether yoga can regress early atherosclerosis in patients with MetS, as measured by carotid intima thickness (cIMT). 100 adult patients of MetS were randomized to yoga and control group and were followed for 1 year. 81% patients completed the study. At the end of 1 year, the yoga group showed a significant regression of cIMT (0.842 ± 0.176 to 0.808 ± 0.204, p<0.001) whereas there was no significant change in cIMT in the control group (0.831 ± 0.171 to 0.834 ± 0.131, p=NS). In addition the yoga group also showed greater reduction in Body Mass Index (BMI), Waist Circumference (WC), LDL cholesterol and Systolic Blood Pressure (SBP). On the basis of this randomized study, we conclude that practice of yoga can regress early atherosclerosis in MetS and has also beneficial effects on several metabolic parameters. The mechanisms of the improvement are not evident from the present study andneed further investigations.

11β-hydroxysteroid dehydrogenase type 1 gene expression is increased in ascending aorta tissue of metabolic syndrome patients with coronary artery disease

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) activity and mRNA levels are increased in visceral and subcutaneous adipose tissues of metabolic syndrome subjects. We analyzed 11β-HSD-1 expression in human epicardial adipose (EA) and ascending aorta (AA) tissues of metabolic syndrome patients and examined their contribution to the development of coronary atherosclerosis. The 11β-HSD-1 expression was evaluated by qRT-PCR in EA and AA tissues of 20 metabolic syndrome patients with coronary artery disease (metabolic syndrome group) and 10 non-metabolic syndrome patients without coronary artery disease (controls). 11β-HSD-1 expression was increased in EA and AA tissues of the metabolic syndrome group (4.1- and 5.5-fold, respectively). A significant positive correlation was found between 11β-HSD-1 expression in EA tissue and waist hip ratio and 11β-HSD-1 expression in AA tissue and body mass index, while a negative correlation was found between 11β-HSD-1 expression in EA tissue and HDL. Expression of CD68, a macrophage marker, was significantly increased in both tissues of the metabolic syndrome group; it was 2-fold higher in AA tissue compared to EA tissue in the metabolic syndrome group. Our findings of increased expression of 11β-HSD-1 and CD68 in AA tissue of the metabolic syndrome group lead us to suggest that they contribute to coronary atherosclerosis in metabolic syndrome. This positive correlation between obesity markers and 11β-HSD-1 in AA and EA tissues strengthens the evidence that 11β-HSD-1 has a role in metabolic syndrome. To the best of our knowledge, this is the first report showing 11β-HSD-1 and CD68 expression in AA tissue of metabolic syndrome patients. We suggest that there is tissue-specific expression of 11β-HSD-1 in metabolic syndrome and associated cardiovascular disorders.

Indicators associated with coronary atherosclerosis in metabolic syndrome

BackgroundMetabolic factors associated with coronary atherosclerosis (CA) in metabolic syndrome (MetS) remain unclear. MethodsA total of 550 consecutive subjects without documented coronary artery disease who received contrast-enhanced coronary computed tomography angiography were analyzed. CA was defined as coronary artery calcification (CAC) scores >0 or, zero CAC score combining noncalcified plaques within the proximal third segment of major coronary arteries. Metabolic factors and novel atherosclerotic biomarkers including high-sensitive C-reactive protein (hs-CRP) and adiponectin were measured. MetS was recognized according to the ethnicity-specific National Cholesterol Educational Program Adult Treatment Panel III, 2001. ResultsAfter adjusted with novel atherosclerotic biomarkers, MetS was significantly associated with CA Odds ratio [OR], 2.88; 95% confidence interval [CI], 1.88 to 4.42; p<0.001). Subgroup analysis revealed that fasting blood glucose ≥110mg/dl/diabetes mellitus in non-MetS subjects (OR, 1.40; 95%CI, 1.08 to 1.82; p<0.05) and total cholesterol (TC)/high density lipoprotein-cholesterol (HDL-C) ≥4.2 in MetS subjects (OR, 4.44; 95%CI, 1.93 to 10.20; p<0.001) were independently associated with CA. Both indicators were significantly associated with increased serum hs-CRP and reduced adiponectin levels in all subjects. ConclusionsMetS is independently associated with CA after adjustment of atherosclerotic biomarkers. TC/HDL-C ≥4.2 in MetS and fasting blood glucose ≥110mg/dl/diabetes mellitus in non-MetS subjects are independent indicators of CA, suggesting the potential difference in pathophysiology of CA.

Insulin Resistance Has Independent Role in Atherogenesis

In conditions with insulin resistance, it is well established that systemic abnormalities, such as dyslipidemia and hypertension, can effect cells in the vascular wall and cause atherosclerosis. Emerging research suggests that insulin resistance within vascular endothelial cells can lead directly to atherosclerosis independently of systemic factors. This effect is large and may be a major determinant of atherosclerosis in metabolic syndrome or type 2 diabetes.

Association of Severity of Osteoarthritis and Carotid Atherosclerosis in Patients with Metabolic Syndrome

Study Background: Increasing evidence in the literature suggests a link between osteoarthritis and atherosclerosis represented by the pro-inflammatory state, independently by concurrent factors such as the joint overload caused by obesity. In this study we examined the role of metabolic syndrome, a cluster of cardiovascular risk factors with a significant pro-inflammatory background, on the severity of both carotid atherosclerosis and osteoarthritis. Methods: We evaluated 68 patients (14 males, 54 females) with (mean±standard error) age and body mass index of 76.99±1.01 years and 27.63±0.62, respectively. The subjects were divided in two groups by the presence of metabolic syndrome (according to Adult Treatment Panel III criteria). Each patient received a score of severity for carotid atherosclerosis (by echo-doppler examination of supra-aortic arteries) and for osteoarthritis (by standard X-ray). The s ites of osteoarthritis was divided in related or not related to weight overload. Results: The body mass index of patients with (n.42) or without metabolic syndrome (n.26) were 28.94±0.84 and 25.87±0.77, respectively (p<0.025). The severity of carotid atherosclerosis were 1.59±0.17 and 0.82±0.18 in the patients with or without metabolic syndrome (p<0.01). The severity of osteoarthritis were 2.59±0.15 and 2.04±0.27 in the patients with or without metabolic syndrome (p=0.06). Metabolic syndrome was significantly related to severity score of carotid atherosclerosis and osteoarthritis (r=0.932 p<0.01 and r=0.936 p<0.01, respectively). Severity score of carotid atherosclerosis and osteoarthritis were significantly related (r=0.895 p<0.05). Conclusion: In this preliminary study, we showed a link between severity of osteoarthritis and atherosclerosis in metabolic syndrome, pointing out the possibility of a common background belonging to the degenerative and inflammatory reactions involving both the cardiovascular and articular system.

Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4

Objective: The accumulation of lipids in macrophages contributes to the development of atherosclerosis. Strategies to reduce lipid accumulation in macrophages may have therapeutic potential for preventing and treating atherosclerosis and cardiovascular complications. The antidiabetic drug metformin has been reported to reduce lipid accumulation in adipocytes. In this study, we examined the effects of metformin on lipid accumulation in macrophages and investigated the mechanisms involved. Methods and results: We observed that metformin significantly reduced palmitic acid (PA)-induced intracellular lipid accumulation in macrophages. Metformin promoted the expression of carnitine palmitoyltransferase I (CPT-1), while reduced the expression of fatty acid-binding protein 4 (FABP4) which was involved in PA-induced lipid accumulation. Quantitative real-time PCR showed that metformin regulates FABP4 expression at the transcriptional level. We identified forkhead transcription factor FOXO1 as a positive regulator of FABP4 expression. Inhibiting FOXO1 expression with FOXO1 siRNA significantly reduced basal and PA-induced FABP4 expression. Overexpression of wild-type FOXO1 and constitutively active FOXO1 significantly increased FABP4 expression, whereas dominant negative FOXO1 dramatically decreased FABP4 expression. Metformin reduced FABP4 expression by promoting FOXO1 nuclear exclusion and subsequently inhibiting its activity. Conclusions: Taken together, these results suggest that metformin reduces lipid accumulation in macrophages by repressing FOXO1-mediated FABP4 transcription. Thus, metformin may have a protective effect against lipid accumulation in macrophages and may serve as a therapeutic agent for preventing and treating atherosclerosis in metabolic syndrome.

Dysfunctional central hemodynamic regulation after daily meal intake in metabolic syndrome

ObjectivePostprandial hyperlipidemia and insulin resistance play roles in the development of atherosclerosis in metabolic syndrome (MetS); however, the clinical significance of postprandial hemodynamic variables in this condition is still in question. The aim of this study was to investigate hemodynamic and metabolic indicators related to MetS after a mixed meal (Calorie mate, 500kcal). MethodsOf 107 participants undergoing this investigation, 24 fulfilled ATPIII criteria for MetS. The remaining 83 subjects were controls. Both the augmentation index (AI) and late systolic blood pressure in the radial artery (rSBP2) as an index of central blood pressure were monitored using HEM-9000AI (Omron Healthcare, Kyoto, Japan) until 240min after meal intake. ResultsBoth AI and rSBP2 showed significant decreases after meal intake in both groups. Changes in postprandial AI showed a similar trend in the groups. rSBP2 reduction 60min after meal ingestion was also comparable, −7.5±2.3mmHg in MetS; −7.8±0.9mmHg in control; however, delta rSBP2-120, the degree of rSBP2 reduction 120min after meal ingestion comparing the fasting level, showed a significant difference between 2 groups, −0.5±2.0mmHg in MetS; −5.3±0.9mmHg in control, P<0.02. Stepwise regression analysis revealed low-density-lipoprotein cholesterol (β=0.333, P=0.001), high-density-lipoprotein cholesterol (β=−0.209, P<0.05) and systolic blood pressure (β=−0.377, P<0.001) as independent variables for determining delta rSBP2-120. ConclusionSubjects with MetS exhibit signs of blunted rSBP2 (=central blood pressure) regulation after food intake. Dysfunctional postprandial hemodynamic regulation is another feature of MetS that may contribute to the progression of cardiovascular disease.

A Short-term Exercise Intervention Reduced Total Matrix Metalloproteinase-9 In Patients With Metabolic Syndrome

Oxidative stress, endothelial cell activation, inflammation and plaque stability are now recognized as important contributors to explain the incidence of atherosclerosis in metabolic syndrome. In this respect it is suggested matrix metalloproteinase (MMP-9) independently predict early risk of cardiovascular disease. Fortunately, recent studies have reported regular exercise may reduce proinflammatory status in patients with metabolic syndrome. On the contrary little attention has been paid regarding plaque destabilization. PURPOSE: For the reasons already mentioned this study was designed to determine the influence of exercise on serum levels of total matrix metalloproteinase-9 (MMP-9) in adult women with metabolic syndrome METHODS: Sixty adult women with metabolic syndrome according to the criteria reported by the National Cholesterol Education Program Adult Treatment Panel III volunteered for this study. Forty-five were randomly included in experimental group to perform a 12-week aerobic training program, 3 days/week, consisting of warm up (10-min), main part (20-35-min [increasing 5 minutes each 3 weeks]) at a work intensity of 60-75% of peak heart rate (increasing 5% each 3 weeks) and cool-down (10min). Control group included 15 age, sex and BMI-matched women with metabolic syndrome that will not perform any program. Written informed consent was obtained. Further our protocol was approved by an institutional ethic committee. Serum total MMP-9 concentration was measured by ELISA, using a commercially available kit (R&D Systems) twice: 72-hours before starting the program (pre-test) and after its ending (post-test). RESULTS: When compared to baseline serum total MMP-9 concentration was decreased significantly after our 12-week protocol (886.3±15.1 vs 609.7±13.2 ng/ml; p<0.05). No changes were reported in controls. CONCLUSIONS: A 12-week training program decreased serum total MMP-9 concentration in adult women with metabolic syndrome. Further studies on this topic are required.

Molecular Mechanisms of Atherosclerosis in Metabolic Syndrome

The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (Irs2) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective Irs2 signaling to MetS-associated alterations. In circulating leukocytes from insulin-resistant MetS patients, Irs2 and Akt2 mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in Irs2 expression in fat-fed apolipoprotein E-null mice lacking one allele of Irs2 (apoE(-/-)Irs2(+/-)) accelerates atherosclerosis compared to apoE-null controls, without affecting plaque composition. Partial Irs2 inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes Akt2 and Ras expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates Mcp1 in VSMCs. Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states.

Comparison of Positive-finding Rates for Subclinical Atherosclerosis in Metabolic Syndrome with Those in Hypercholesterolemia

Comparison of Positive-finding Rates for Subclinical Atherosclerosis in Metabolic Syndrome with Those in Hypercholesterolemia

Abstract 394: Posttranslational Modification Of Klf5 Mediates Metabolic Dysfunction And Vascular Disease In Metabolic Syndrome

We have previously shown that a zinc finger transcription factor, Krüppel-like factor 5 (KLF5), plays an important role in pathogenesis of cardiovascular diseases, such as atherosclerosis. KLF5 heterozygous knockout ( KLF5 +/ − ) mice exhibited much less neointima formation, cardiac hypertrophy and fibrosis. We also found that expression of KLF5 correlated with a higher incidence of restenosis following PCI and the SNP located within the KLF5 promoter was associated with an increased risk of hypertension in man. Interestingly, KLF5 is also expressed in metabolic tissues such as adipose tissue, skeletal muscle, and pancreatic β-cells. Thus, we hypothesized that KLF5 might play a role in metabolic diseases. To test this, KLF5 +/ − mice were fed with high-fat diet. Although KLF5 +/ − mice ate more food than wild-type littermates, they were resistant to high-fat diet-induced obesity and protected from dyslipidemia, glucose intolerance and hepatic steatosis, indicating that KLF5 + /− mice were less susceptible to metabolic syndrome. The systemic O 2 consumption and expression of genes involved in energy expenditure in skeletal muscle were increased in KLF5 + /− mice, demonstrating enhanced energy expenditure, which partly explains the phenotype. Knocking down KLF5 by siRNA increased expression levels of UCP2/3 and CPT-1b in C2C12 myotubes, suggesting that KLF5 may inhibit energy expenditure-related genes. Chromatin immunoprecipitation and coimmunoprecipitation assays showed that KLF5 interacted with corepressors, such as SMRT and NCoR, and strongly inhibited the UCP and CPT-1b promoters. We found that this inhibitory activity of KLF5 depended on its SUMOylation. When KLF5 was deSUMOylated, it activated the promoters. These data demonstrate that KLF5 acts as a molecular switch for energy expenditure and the posttranslational modifications of KLF5 including SUMOylation turns on/off the switch function of KLF5. Given that KLF5 also controls tissue remodeling in response to external stress, KLF5 may mediate metabolic dysfunction and atherosclerosis in metabolic syndrome. Our findings also suggest that the posttranscriptional modification of KLF5 is an attractive novel therapeutic target.

Intimal redox stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy

Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting in the production of reactive oxygen species. The redox stress associated with these reactive oxygen species contribute to the development, progression, and the final fate of the arterial vessel wall in prediabetic and diabetic atheroscleropathy. The prevention of morbidity and mortality of these intersecting metabolic diseases can be approached through comprehensive global risk reduction.