Metabolic Syndrome In Rats Research Articles

Effects of Combination of Carvedilol and Melatonin on Induced Metabolic Syndrome in Rats

Background: The prevalence of metabolic syndrome is increasing and it is considered one of the main threats to human health worldwide. Fructose feeding induces hyper-insulinemia, insulin resistance and hyper-triglyceridemia. The main objective of the present study is to evaluate the pharmacological effects of the single and combined administration of carvedilol and melatonin in fructose-induced metabolic syndrome in rats. Methods: Male albino rats were fed a high fructose diet for ten weeks to induce metabolic syndrome. Oral administration of carvedilol (20 mg/kg/day), melatonin (10 mg/kg/day), carvedilol and melatonin (20 mg +10 mg/kg/ day) or vehicle was conducted for six weeks after stopping the high fructose feeding.Indices of systolic blood pressure (SBP), Fasting Blood Glucose (FBG), Fasting Serum Insulin (FSI), serum lipid profiles, serum Nitric Oxide (NO), serum lipid peroxides as well as levels of total antioxidants were determined. Insulin resistance index were calculated from FBG and FSI using HOMA-IR (Homeostasis Model Assessment). Results: A high-fructose diet was associated with hypertension, dyslipidemia, insulin resistance, decreased nitrite and increased of oxidative stress. Carvedilol, melatonin or combination of carvedilol and melatonin was able to reverse features of metabolic syndrome in the six weeks. The intensity of changes produced by melatonin was of greater extent in insulin resistance and lipid profiles than produced by carvedilol but the effect of carvedilol was higher in hypertension. The combination of carvedilol plus melatonin was superior of the others. Conclusion: A combination of both carvedilol (20 mg/kg/ day orally) and melatonin (10 mg/kg/ day orally) for 6 weeks revealed a statistical significant results in comparison to carvedilol (20 mg/kg/ day orally) or melatonin (10 mg/kg/ day orally) alone. A combination of carvedilol and melatonin may give an additive effect better than each of them alone.

Potential protective effects of Nigella sativa and Allium sativum against fructose-induced metabolic syndrome in rats.

Among famous medicinal plants with known antioxidant activity; black seed (Nigella sativa, NS) and garlic (Allium sativum) which have been used in traditional medicine. In recent years, rates of metabolic syndrome (MS) have been increasing globally. The present work was designed to study the potential protective effects of black seed and raw garlic homogenate against fructose-induced MS in rats and to assess the benefits gained from their combination. Fifty male albino Wistar rats were divided into 5 groups. A control group was allowed to feed on normal chow and drink tap water. MS group was fed the same diet plus 10% fructose in drinking water. Treated groups received NS or garlic either alone or in combination as oral supplements along with high fructose diet for 8 weeks. Results revealed that body weight, liver weight, fasting blood glucose, serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were significantly increased while high density lipoprotein cholesterol (HDL-C) and the activities of Lactate dehydrogenase (LDH), glucose -6-phosphate dehydrogenase (G-6-PHD) and catalase in liver tissues were significantly decreased in MS group compared to the control group. Administration of NS or garlic either alone or in combination significantly ameliorated all the above-mentioned altered parameters. Treatment with both NS and garlic showed the utmost reduction in serum LDL-C and TG levels and could restore the activities of the studied enzymes in liver nearly to normal values. It was concluded that both NS and garlic were effective in attenuating multiple abnormalities of MS. Combination of these medicinal plants may have additional effectiveness in reducing serum TC, LDL-C and increasing HDL-C levels which could be a step in the prevention and management of MS.

Effects of carvedilol and melatonin on fructose-induced metabolic syndrome in rats

Effects of carvedilol and melatonin on fructose-induced metabolic syndrome in rats

The establishment of metabolic syndrome model by induction of fructose drinking water in male Wistar rats.

Background. Metabolic syndrome can be caused by modification of diet by means of consumption of high carbohydrate and high fat diet such as fructose. Aims. To develop a metabolic syndrome rat model by induction of fructose drinking water (FDW) in male Wistar rats. Methods. Eighteen male Wistar rats were fed with FDW 20% and FDW 25% for a duration of eight weeks. The physiological changes with regard to food and fluid intake, as well as calorie intake, were measured. The metabolic changes such as obesity, dyslipidaemia, hypertension, and hyperglycaemia were determined. Data was presented in mean ± SEM subjected to one-way ANOVA. Results. Male Wistar rats fed with FDW 20% for eight weeks developed significant higher obesity parameters compared to those fed with FDW 25%. There was hypertrophy of adipocytes in F20 and F25. There were also systolic hypertension, hypertriglyceridemia, and hyperglycemia in both groups. Conclusion. We conclude that the metabolic syndrome rat model is best established with the induction of FDW 20% for eight weeks. This was evident in the form of higher obesity parameter which caused the development of the metabolic syndrome.

Montelukast and irbesartan ameliorate metabolic and hepatic disorders in fructose-induced metabolic syndrome in rats

Metabolic syndrome (MetS) is a global health problem. Elucidation of the role of 5- lipooxygenase/leukotriene pathway and renin angiotensin system in the pathogenesis of MetS suggests a variety of potential therapies worthy of testing. The present work investigated the effect of montelukast, a leukotriene antagonist and/or irbesartan, an angiotensin II-receptor blocker, in the prevention of fructose-induced MetS in rats. Rats were allocated into 9 groups and treated for 6 weeks as follow: normal control; MetS group (received 20% fructose); MetS+montelukast groups (treated with montelukast, 5, 10, and 20mg/kg/day, respectively); MetS+irbesartan groups (treated withirbesartan 15, 30, and 45mg/kg/day, respectively); and MetS+montelukast+irbesartan group (co treated with montelukast 5mg/kg plus irbesartan 15mg/g). Metabolic parameters (visceral fat index, liver index, insulin resistance, and serum lipid profile), oxidative stress markers (malondialdehyde, reduced glutathione, and catalase), and inflammatory mediators (tumor necrosis factor-α, and uric acid) were measured. Expression of caspase-3 in hepatic tissues was detected by immunohistochemistry. Liver injury was evaluated by histopathological examination and serum alanine aminotransferase (ALT). Montelukast, irbesartan, and their combination caused significant attenuation in metabolic and hepatic disorders. Their effect was associated with attenuation of oxidative stress markers, inflammatory mediators, and caspase-3 expression. This study highlighted the protective effects of montelukast and irbesartan against fructose-induced metabolic and hepatic disorders. The protective effect of either drug relies, at least in part, on their antioxidant and antiinflammatory effect, as well as on the reduction of caspase-3 expression in hepatic tissue.

Pharmacokinetic comparisons of berberine and palmatine in normal and metabolic syndrome rats

Ethnopharmacological relevanceSan-Huang formula is a popular traditional Chinese medicine (TCM) preparation to replenish Qi, resolve phlegm, dissipate blood stasis, and therapy metabolic syndrome in China. Metabolic syndrome, which is accompanied by Qi and blood stasis, mainly arises from spleen deficiency in essence. There is limited information available for differences of pharmacokinetic properties of San-Huang formula between normal and metabolic syndrome rats. The present study was conducted to compare the pharmacokinetics of berberine as well as palmatine in normal and metabolic syndrome rats following oral administration of San-Huang formula extract. Materials and methodsThe animals were orally administered with San-Huang formula extract with the equivalent dose of 60.4 and 12.5mg/kg for berberine and palmatine, respectively. The blood samples were collected according to the time schedule. The concentrations of berberine and palmatine in rat plasma were determined by LC–ESI/MS. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods. ResultsIt was found that AUC0−t, Cmax, Vd and CL of berberine and palmatine in metabolic syndrome rats were significantly different (P<0.05) from normal rats. ConclusionsThe results indicated that berberine and palmatine have higher uptake and slower elimination in the rats with metabolic syndrome, which suggests that the rate and extent of drug metabolism were altered in metabolic syndrome rats.

Metabolic Syndrome Remodels Electrical Activity of the Sinoatrial Node and Produces Arrhythmias in Rats

In the last ten years, the incidences of metabolic syndrome and supraventricular arrhythmias have greatly increased. The metabolic syndrome is a cluster of alterations, which include obesity, hypertension, hypertriglyceridemia, glucose intolerance and insulin resistance, that increase the risk of developing, among others, atrial and nodal arrhythmias.The aim of this study is to demonstrate that metabolic syndrome induces electrical remodeling of the sinus node and produces arrhythmias. We induced metabolic syndrome in 2-month-old male Wistar rats by administering 20% sucrose in the drinking water. Eight weeks later, the rats were anesthetized and the electrocardiogram was recorded, revealing the presence of arrhythmias only in treated rats. Using conventional microelectrode and voltage clamp techniques, we analyzed the electrical activity of the sinoatrial node.We observed that in the sinoatrial node of “metabolic syndrome rats”, compared to controls, the spontaneous firing of all cells decreased, while the slope of the diastolic depolarization increased only in latent pacemaker cells. Accordingly, the pacemaker currents If and Ist increased. Furthermore, histological analysis showed a large amount of fat surrounding nodal cardiomyocytes and a rise in the sympathetic innervation. Finally, Poincaré plot denoted irregularity in the R-R and P-P ECG intervals, in agreement with the variability of nodal firing potential recorded in metabolic syndrome rats.We conclude that metabolic syndrome produces a dysfunction SA node by disrupting normal architecture and the electrical activity, which could explain the onset of arrhythmias in rats.

Age-dependent effect of high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney of rats

BackgroundThe metabolic syndrome (MS) is characterized by variable coexistence of metabolic and pathophysiological alterations which are important risk factors for developing of type II diabetes and/or cardiovascular diseases. Increased of MS patients in worldwide has stimulated the development of experimental models. However, it is still challenging to find an dietetic model that most closely approximates human MS and, in addition, is not yet fully established the effect of different diets of MS in lipid metabolism in rats of different ages. The aim of this study was to evaluate the effect of different diets of MS in lipid metabolism and ectopic fat deposition and define the most appropriate diet for inducing the characteristic disturbances of the human MS in rats of different ages.MethodsYoung (4 weeks old) and adult rats (12 weeks old) were given a high-fat (FAT) or high-fructose diet (FRU) for 13 weeks and biochemical, physiological, histological and biometric parameters were evaluated.ResultsIn young rats, the FAT diet induced increased mean blood pressure (MAP) and heart rate (HR), body weight after 6 to 10 weeks, and in the 13th week, increased the liver, mesenteric, retroperitoneal and epididymal fat weights, fasting glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and reduced HDL cholesterol; and also induced non-alcoholic fatty liver disease (NAFLD) and renal inflammatory infiltrates. In adult rats, the FRU diet induced transient elevations of MAP and HR in the 6th week, and, at 13 weeks, increased fasting glucose, triglycerides, total cholesterol, AST and ALT; increased liver, kidneys and retroperitoneal fat weights; and induced macrovesicular and microvesicular NAFLD, the presence of fat cells in the kidney, glomerular sclerosis, and liver and kidney inflammation. Additionally, the FAT and FRU diets induced, respectively, increases in liver glycogen in adults and young rats.ConclusionsOur data show that FRU diet in adult rats causes biggest change on metabolism of serum lipids and lipid accumulation in liver and kidney, while the FAT diet in young rats induces elevation of MAP and HR and higher increased visceral lipid stores, constituting the best nutritional interventions to induce MS in rats.

Correction to “A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats”

Correction to “A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats”

Metabolomics study of hydroxytyrosol's administration in a metabolic syndrome rat model

Metabolic syndrome is a clustering of interrelated risk factors for cardiovascular disease and diabetes. The Mediterranean diet has been proposed as an important dietary pattern to confer cardioprotection by attenuating risk factors of metabolic syndrome. Hydroxytyrosol (HT) is a single phenol present in large amount in olive byproducts and in lower amounts in olive oil and in olive fruits, which are basic constituents of the Mediterranean diet. In the context of identifying the features of HT that are responsible for its effects on the metabolic syndrome, an experimental protocol has been setup encompassing isolated HT administration in a diet induced model of metabolic syndrome in young Wistar rats. Rats were randomly divided into four groups as cornstarch (CS), cornstarch + HT (CSHT), high-carbohydrate high-fat (HF) and high-carbohydrate high-fat + HT (HFHT) (n = 6/group). HT (20 mg/kg/d oral gavage, water vehicle) was administered for 8 weeks on the basal diet (CS or HF). In order to gain insight on the metabolic effects of HT administration on the total biochemical profile (metabolome), an untargeted approach (metabolomics) has been developed and attempted on the rat plasma and urine samples from the metabolic syndrome model. The new biomarkers discovered from multivariate analysis have been identified by comparison with public domain metabolome libraries but also by confirmation using HRMS/MS, highlighting the differences in the biochemistry of HFHT animals versus controls as well as versus CSHT. Fatty acid metabolism was found to be down regulated in HFHT rats while glycerol, which releases from triacylglycerols, was the main up regulated metabolite in HFHT rats and correlates to fatty acid transportation catabolism. HT supplementation for 8 weeks reduced visceral obesity and was associated with improved left ventricular structure and function, reduced blood pressure, improved glucose disposal and reduced hepatic steatosis.

Hyperglycemia Accelerates Apparent Diffusion Coefficient-Defined Lesion Growth after Focal Cerebral Ischemia in Rats with and Without Features of Metabolic Syndrome

Poststroke hyperglycemia is associated with a poor outcome yet clinical management is inadequately informed. We sought to determine whether clinically relevant levels of hyperglycemia exert detrimental effects on the early evolution of focal ischemic brain damage, as determined by magnetic resonance imaging, in normal rats and in those modeling the 'metabolic syndrome'. Wistar Kyoto (WKY) or fructose-fed spontaneously hypertensive stroke-prone (ffSHRSP) rats were randomly allocated to groups for glucose or vehicle administration before permanent middle cerebral artery occlusion. Diffusion-weighted imaging was carried out over the first 4 hours after middle cerebral artery occlusion and lesion volume calculated from apparent diffusion coefficient maps. Infarct volume and immunostaining for markers of oxidative stress were measured in the fixed brain sections at 24 hours. Hyperglycemia rapidly exacerbated early ischemic damage in both WKY and ffSHRSP rats but increased infarct volume only in WKY rats. There was only limited evidence of oxidative stress in hyperglycemic animals. Acute hyperglycemia, at clinically relevant levels, exacerbates early ischemic damage in both normal and metabolic syndrome rats. Management of hyperglycemia may have greatest benefit when performed in the acute phase after stroke in the absence or presence of comorbidities.

Melatonin and diet-induced metabolic syndrome in rats: impact on the hypophysial-testicular axis.

Abstract Combinations of fructose- and fat-rich diets in experimental animals can model the human metabolic syndrome (MS). In rats, the increase in blood pressure (BP) after diet manipulation is sex related and highly dependent on testosterone secretion. However, the extent of the impact of diet on rodent hypophysial-testicular axis remains undefined. In the present study, rats drinking a 10% fructose solution or fed a high-fat (35%) diet for 10 weeks had higher plasma levels of luteinizing hormone (LH) and lower plasma levels of testosterone, without significant changes in circulating follicle-stimulating hormone or the weight of most reproductive organs. Diet manipulation brought about a significant increase in body weight, systolic BP, area under the curve (AUC) of glycemia after an intraperitoneal glucose tolerance test (IPGTT), and plasma low-density lipoprotein cholesterol, cholesterol, triglycerides, and uric acid levels. The concomitant administration of melatonin (25 μg/mL of drinking water) normalized the abnormally high LH levels but did not affect the inhibited testosterone secretion found in fructose- or high-fat-fed rats. Rather, melatonin per se inhibited testosterone secretion. Melatonin significantly blunted the body weight and systolic BP increase, the increase in the AUC of glycemia after an IPGTT, and the changes in circulating lipid profile and uric acid found in both MS models. The results are compatible with a primary inhibition of testicular function in diet-induced MS in rats and with the partial effectiveness of melatonin to counteract the metabolic but not the testicular sequelae of rodent MS.

Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes

OBJECTIVES:We evaluated the effects of aerobic exercise training without dietary changes on cardiovascular and metabolic variables and on the expression of glucose transporter Type 4 in rats with metabolic syndrome.METHODS:Twenty male spontaneously hypertensive rats received monosodium glutamate during the neonatal period. The animals were allocated to the following groups: MS (sedentary metabolic syndrome), MS-T (trained on a treadmill for 1 hour/day, 5 days/week for 10 weeks), H (sedentary spontaneously hypertensive rats) and H-T (trained spontaneously hypertensive rats). The Lee index, blood pressure (tail-cuff system), insulin sensitivity (insulin tolerance test) and functional capacity were evaluated before and after 10 weeks of training. Glucose transporter Type 4 expression was analyzed using Western blotting. The data were compared using analysis of variance (ANOVA) (p<0.05).RESULTS:At baseline, the MS rats exhibited lower insulin sensitivity and increased Lee index compared with the H rats. Training decreased the body weight and Lee index of the MS rats (MS-T vs. MS), but not of the H rats (H-T vs. H). There were no differences in food intake between the groups. At the end of the experiments, the systolic blood pressure was lower in the two trained groups than in their sedentary controls. Whole-body insulin sensitivity increased in the trained groups. Glucose transporter Type 4 content increased in the heart, white adipose tissue and gastrocnemius muscle of the trained groups relative to their respective untrained groups.CONCLUSION:In conclusion, the present study shows that an isolated aerobic exercise training intervention is an efficient means of improving several components of metabolic syndrome, that is, training reduces obesity and hypertension and increases insulin sensitivity.

Huang-Lian-Jie-Du-Tang Protects Rats from Cardiac Damages Induced by Metabolic Disorder by Improving Inflammation-Mediated Insulin Resistance

Huang-lian-jie-du-tang (HLJDT), a traditional Chinese medicine, has been shown to improve insulin resistance (IR) induced by inflammation, a key event in the development of metabolic syndrome (MS). The present study aimed to investigate the protective effects of HLJDT on MS and explore the underlying mechanism. MS rats were established with obese-diets and treated with normal saline, aspirin or HLJDT. The myocardial lesions were identified by echocardiogram, transmission electron microscope, and Sirius-red staining. The inflammatory cytokines were measured by ELISA and real-time PCR. The activation of NF-κB, JNK, SOCS3, IRS1 and AKT in the heart was detected by immunohistochemistry and Western blot analysis. Compared with the controls, MS rats developed obvious obesity, hypertension, dyslipidemia, IR, inflammation, and cardiac damage. Moreover, phosphorylated IRS-1 at Ser307 was correlated with the activation of NF-κB, JNK and SOCS3 and the inhibition of AKT in the heart from MS rats. These data suggest that serine phosphorylation of IRS-1 in response to inflammation is mediated, in part, by NF-κB, JNK and SOCS3. Notably, HLJDT inhibited the activation of NF-κB and reduced serine phosphorylation of IRS-1. In summary, HLJDT protects myocardium from IR-mediated injury by inhibiting serine phosphorylation of IRS-1 in MS rats.

Modification of the liver fatty acids by Hibiscus sabdariffa Linnaeus (Malvaceae) infusion, its possible effect on vascular reactivity in a metabolic syndrome model

We investigated the effects of Hibiscus sabdariffa Linnaeus (HSL)-fed infusion on the fatty acid (FA) profile in liver of metabolic syndrome (MS) rats and its possible effect on vascular reactivity. Body mass, intra-abdominal fat, triglycerides, insulin, blood pressure, saturated, monounsaturated FA, NEFAs, Δ9-, Δ6-desaturases and vasoconstriction were increased, while vasorelaxation, polyunsaturated FA, endothelial nitric oxide and / ratio decreased in MS versus Control, but HSL infusion modified it and increased Δ5-desaturase. The results suggest that the alteration in FA liver metabolism in the MS contributes to impaired vascular reactivity, but treatment with of HSL infusion can improve this condition.

Pioglitazone enhances the blood pressure-lowering effect of losartan via synergistic attenuation of angiotensin II-induced vasoconstriction

This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats. An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT1), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox), level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected. After eight weeks of treatment, the SBP and MAP in the losartan (115 ± 5 and 106 ± 6 mmHg), pioglitazone (130 ± 6 and 118 ± 6 mmHg), and combination therapy (105 ± 6 and 98 ± 5 mmHg) groups were lower than those in the model group (150 ± 8 and 136 ± 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47(phox) and AT1, NADPH oxidase activity, and nitrotyrosine level. Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions.

Influence of Coffee Brew in Metabolic Syndrome and Type 2 Diabetes

This study aimed to evaluate the effect of coffee drinking on clinical markers of diabetes and metabolic syndrome in Zucker rats. Diabetic Zucker rats with metabolic syndrome and control Zucker rats were used for in vivo tests. The animals received daily doses of coffee drink by gavage for 30 days. After the treatment, the levels of glucose, triglycerides, total cholesterol and fractions, creatinine, uric acid, activity of aspartate aminotransferase and alanine aminotransferase were evaluated. Urea and creatinine levels were also analyzed in urine. By collaborating in the modulation of the metabolic syndrome and diabetes mellitus type 2, coffee drink helped in reducing serum glucose, total cholesterol and triglycerides. The results demonstrate that treatment with roasted coffee drink, because of its hypoglycemic and hypolipidemic effect, is efficient in the protection of animals with metabolic syndrome and diabetes mellitus type 2.

Abstract 264: Edaravone Injected at the Start of Reperfusion Suppresses Lung Damage Caused by Myonephropathic Metabolic Syndrome in Rats

Introduction &amp; Hypothesis Free radicals have been implicated in myonephropathic metabolic syndrome (MNMS), which damages not only muscles but also lungs. At ATVB 2012, we previously reported that radical scavenger, edaravone (Radicut®, Mitsubishi Tanabe Pharma Co., Japan) injected at the start of reperfusion suppresses muscle injury following leg ischemia in rats. In this study, we evaluated whether edaravone can suppress MNMS-induced lung damage following leg ischemia, if injected at the start of reperfusion. Methods The MNMS models (Male Lewis rats, 525 ± 78 g, n = 10) were induced, by clamping the bilateral common femoral arteries for 5 hours and then de-clamping. The rats were intraperitoneally injected with either 9.0 mg / kg of edaravone (edaravone group; n = 5), or saline (MNMS group; n = 5) at the same time as de-clamping, corresponding to the start of reperfusion. Five hours after de-clamping, the both lungs were harvested and stained with hematoxylin &amp; eosin (HE). Normal lungs without reperfusion were also harvested as control (n = 3). Lung damage was expressed as the percentage area of the alveolar wall thickness, determined by computerized densitometry (NIH Image Program J, Ver. 1.37). Results The lungs of MNMS group had extensive swelling. But the lungs of the edaravone group were filled with air, similar to that of normal lungs (Figure attached, original 200x). The mean percentage area in the edaravone group was significantly lower than that in MNMS group (17.2 ± 5.2 vs. 63.6 ± 5.6%, p &lt; 0.001). Conclusions Our results suggest that edaravone injected at the start of reperfusion can suppress MNMS-induced lung damage following leg ischemia in rats.

Impaired Coronary Collateral Growth in the Metabolic Syndrome Is in Part Mediated by Matrix Metalloproteinase 12–Dependent Production of Endostatin and Angiostatin

We have previously shown that transient coronary artery occlusion stimulated coronary collateral growth (CCG) in healthy (Sprague Dawley) but not in metabolic syndrome (JCR:LA-cp [JCR] ) rats. Here, we sought to determine whether matrix metalloproteinases (MMPs) negatively regulate CCG in the metabolic syndrome via release of endostatin and angiostatin. Rats underwent transient, repetitive left anterior descending occlusion and resultant myocardial ischemia (RI) for 0 to 10 days. CCG was measured in the collateral-dependent and normal zones using microspheres, MMP activation by Western blot, and endostatin and angiostatin by ELISA on days 0, 3, 6, 9, or 10 of RI. Endostatin and angiostatin were increased in JCR but not in Sprague Dawley rats on days 6 and 9 of RI. Increased endostatin and angiostatin correlated with increased MMP12 (≈ 4-fold) activation in JCR but not in Sprague Dawley rats on days 6 and 9 of RI. Inhibition of MMP12 in JCR rats nearly completely blocked endostatin (≈ 85%) and angiostatin (≈ 90%) generation and significantly improved CCG (collateral-dependent zone flow was ≈ 66% of normal zone flow versus ≈ 12% for JCR RI). Compromised CCG in the metabolic syndrome is, in large part, because of increased MMP12 activation and consequent increased generation of endostatin and angiostatin, which inhibits late-stage collateral remodeling.

Excessive vascular smooth muscle and macrophage proliferation underlies impaired coronary collateral growth in the metabolic syndrome

RationaleCoronary collateral growth (CCG) is impaired in the metabolic syndrome. It is thought that inadequate cell proliferation is a causative factor. Pro‐angiogenic growth factors (GFs) stimulate cell proliferation. Metabolic syndrome patients and animal models exhibit elevated GF levels, but administration of GFs does not promote CCG in the metabolic syndrome.ObjectiveTo determine whether temporally inappropriate excessive cell proliferation underlies impaired CCG in the metabolic syndrome.Methods and ResultsNormal (SD) and metabolic syndrome (JCR) rats underwent transient, repetitive coronary artery occlusion (RI). We have previously shown that CCG was maximal at day 9 of RI in SD rats but did not occur in JCR rats. Cell proliferation was evaluated by immunohistochemistry (PCNA, Ki‐67) and Western blotting (PCNA). The increase in cell proliferation was transient in SD but greater and sustained in JCR rats. Assessment of cell cycle progression confirmed early and transient cell proliferation in SD vs. sustained proliferation in JCR rats. This was associated with accumulation of proliferating cells in the lumen of small arterioles in JCR rats, which failed to undergo outward expansion.ConclusionsExcessive cell proliferation in the later stages of collateral remodeling underlies impaired CCG in the metabolic syndrome. R01 HL093052