Chronic Production of Peroxynitrite in the Vascular Wall Impairs Vasorelaxation Function in SHR/NDmcr-cp Rats, an Animal Model of Metabolic Syndrome

Kagota, Satomi; Tada, Yasuyuki; Nejime, Namie; Nakamura, Kazuki; Kunitomo, Masaru; Shinozuka, Kazumasa

doi:10.1254/jphs.08273fp

Cited by 32 publications

(31 citation statements)

References 40 publications

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“…In previous studies we have proposed that peroxynitrite played a critical role in development of cardiovascular events in SHRSP-fatty. 8,[34][35][36][37] Additional studies are needed to be clarified involvement of MMPs, MLC-1 and peroxynitrite in progression of ventricular diastolic dysfunction in SHRSPfatty.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Tada

Kagota

Matsumoto

et al. 2010

Biological & Pharmaceutical Bulletin

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Lifestyle-related diseases-visceral obesity, hypertension, dyslipidemia and glucose intolerance-are known to appear in a cluster referred to as metabolic syndrome. As the number of disease components in metabolic syndrome increases in a patient, the structure and function of the heart becomes more compromised. 1) For example, metabolic syndrome increases the risk of atrial enlargement and fibrillation 2,3) and left ventricular hypertrophy and diastolic dysfunction. 1,4) These structural and functional abnormalities are considered to contribute to the increased cardiovascular morbidity and mortality associated with metabolic syndrome. However, the mechanisms underlying these abnormalities are not well understood.SHRSP.Z-Lepr fa /IzmDmcr rats (SHRSP-fatty) were established by crossing stroke-prone SHR (SHRSP/Izm) with Zucker obese rats to create a new animal model of metabolic syndrome.5) These rats develop spontaneous severe hypertension and obesity, and exhibit metabolic abnormalities (dyslipidemia, hyperinsulinemia and hyperglycemia), which are similar to those found in human metabolic syndrome. To date SHRSP-fatty have been used in studies that evaluated dysfunction of vasodilation mechanisms, cardiovascular remodeling, and atherogenic dyslipidemia in metabolic syndrome. [6][7][8] The aim of the present study was to characterize the cardiac structure and function in SHRSP-fatty. Increased cardiac stiffness induced by disturbed myocardial collagen turnover is suggested as one of the mechanisms of cardiac abnormalities in hypertension and diabetes.9,10) Therefore, as structural parameters, heart weight and a major myocardial collagen, collagen type I, as an index of fibrosis, were measured. Additionally, collagen type III, which contributes to tissue elasticity, was measured and the ratio of type I to type III was calculated as an index of myocardial stiffness. To assess cardiac function in SHRSP-fatty, heart rate, systolic blood pressure, cardiac output, blood flow and stroke volume were measured by tail-cuff and plethysmography, and compared to those in hypertensive lean SHRSP and normotensive lean WistarKyoto rats (WKY). Systolic and diastolic cardiac functions were also determined by echocardiography. The results may inform us whether this model would be a useful animal model to evaluate cardiac complications of metabolic syndrome. MATERIALS AND METHODS Experimental AnimalsMale SHRSP-fatty (nϭ18), SHRSP (nϭ18) and normotensive control WKY (nϭ18) were purchased at 16 weeks of age from Japan SLC, Inc. (Hamamatsu, Japan). The rats were established by the Disease Model Cooperative Research Association (Hamamatsu, Japan). Standard chow (CE-2; Clea Japan Inc., Tokyo, Japan) and water were available ad libitum during the experimental period. The study protocols were performed according to the Guideline for the Care and Use of Laboratory Animals approved by Mukogawa Women's University.Tail-Cuff Method and Plethysmography Systolic blood pressure and heart rate of conscious rats were meas- Cardiac structural and funct...

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Section: Discussionmentioning

confidence: 99%

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Tada

Kagota

Matsumoto

et al. 2010

Biological & Pharmaceutical Bulletin

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“…On the other hand, by 17 -18 weeks, body weight, blood pressure, plasma triglyceride, blood glucose, and plasma insulin were all significantly higher in SHR/NDmcr-cp than in WKY at 17 -18 weeks of age. Thus, this stage is thought to represent a time after the development of metabolic syndrome (17,18). In the present study, we used SHR/NDmcr-cp rats at an early stage of metabolic syndrome development (13 weeks).…”

Section: Discussionmentioning

confidence: 99%

Irbesartan Prevents Metabolic Syndrome in Rats via Activation of Peroxisome Proliferator-Activated Receptor γ

2011

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Abstract. Irbesartan, an angiotensin-receptor blocker, is a known agonist of peroxisome proliferator-activated receptor (PPAR) γ. In this study, thirteen-week-old spontaneously hypertensive (SHR)/NDmcr-cp rats, representing a genetic model of metabolic syndrome, were treated daily with placebo, irbesartan (30 mg/kg), valsartan (10 mg/kg), or pioglitazone (10 mg/kg) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-and valsartan-treated groups, but not in the pioglitazone-treated group. Compared with the placebo group, plasma insulin, homeostasis model assessment of insulin resistance index, and plasma triglyceride levels were significantly lower while plasma adiponectin levels were significantly higher in the pioglitazone-and irbesartan-treated groups, but not in the valsartan-treated group. Significant increases in the gene expression of adiponectin and GLUT4 within adipose tissue were also observed in the pioglitazone-and irbesartan-treated groups, but not in the valsartan-treated group. These findings suggest that through PPARγ stimulation along with angiotensin II inhibition, irbesartan may be an optimal treatment option in the prevention of metabolic syndrome as well as hypertension.

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“…6) Therefore, when the balance or regulation between the rinse in cholesterol uptake and reduction in cholesterol biosynthesis of liver disappears from 10 weeks of age onward, SHR-cp may develop hypercholesteremia.…”

Section: Genesmentioning

confidence: 99%

“…2) The serum total cholesterol level in SHR-cp at 18 weeks of age is higher than that of Wistar Kyoto rat (WKY), 6) but that in SHR-cp at 10 weeks of age is the same.…”

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confidence: 97%

“…5) SHR-cp was reported to show hypercholesteremia and hyperglyceridemia, as compared with lean littermates (SHR-ln) that have hypertension.2) The serum total cholesterol level in SHR-cp at 18 weeks of age is higher than that of Wistar Kyoto rat (WKY), 6) but that in SHR-cp at 10 weeks of age is the same.7) It remains unclear whether there are differences in the system regulating serum cholesterol levels between SHRcp and WKY at 10 weeks of age. Thus, we compared cholesterol levels in serum and liver between SHR-cp and WKY.…”

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confidence: 99%

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Comparison of Receptors and Enzymes Regulating Cholesterol Levels in Liver between SHR/NDmcr-cp Rats and Normotensive Wistar Kyoto Rats at Ten Weeks of Age

Michihara

Anraku

Abe

et al. 2011

Biological & Pharmaceutical Bulletin

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Spontaneously hypertensive rat (SHR)/NDmcr-cp (cp/cp) rat (SHR-cp) is a congenic SHR rat with nonsense mutation introduced into the leptin receptor.1) Metabolic syndrome, characterized by the concomitant presence of obesity, hypertension, hyperlipidemia and diabetes, develops spontaneously in the SHR-cp, 2-4) along with age-related histologically evident glomerular injury and tubulointerstitial damage, including mesangial activation, podocyte injury, and inflammatory cell infiltration in the tubulointerstitium. 5) SHR-cp was reported to show hypercholesteremia and hyperglyceridemia, as compared with lean littermates (SHR-ln) that have hypertension.2) The serum total cholesterol level in SHR-cp at 18 weeks of age is higher than that of Wistar Kyoto rat (WKY), 6) but that in SHR-cp at 10 weeks of age is the same.7) It remains unclear whether there are differences in the system regulating serum cholesterol levels between SHRcp and WKY at 10 weeks of age. Thus, we compared cholesterol levels in serum and liver between SHR-cp and WKY. Furthermore, mRNA levels of receptors or enzymes involved in uptake from serum to liver, cholesterol catabolism, or cholesterol biosynthesis in liver were compared between SHR-cp and WKY. MATERIALS AND METHODS MaterialsThe Cholesterol E-test Wako was obtained from Wako (Osaka, Japan). The high density lipoprotein (HDL) and very low density lipoprotein (VLDL)/low density lipoprotein (LDL) Quantification Kit was from BioVision, Inc. The Biomasher was obtained from Assist (Tokyo, Japan), QuickGene RNA tissue kit SII from Fujifilm (Tokyo, Japan), and SYBR Ex Script reverse transcription-polymerase chain reaction (RT-PCR) kit from TaKaRa (Shiga, Japan). All other chemicals were of reagent grade and purchased commercially.Animals Male (6-week-old) WKY and SHR-cp were obtained from the Disease Model Co-operative Research Association, Japan. The rats were fed standard chow for 4 weeks and used at 10 weeks of age. The experimental protocol was reviewed and approved by the Animal Care and Use Committee of Fukuyama University.Cholesterol Levels in Liver and Serum One hundred milligrams of liver was homogenized in 500 ml of homogenization buffer (50 mM Tris-HCl, pH 7.5 containing 0.5 mM phenylmethylsulfonyl fluoride (PMSF), 10 mM 2-mercaptoethanol, 1 mM ethylenediaminetetraacetic acid (EDTA), and protease inhibitors [1 mM leupeptin, 1 mM pepstatin A, 1 mM chymostatin, and 1 mM antipain]) and centrifuged at 1000ϫg for 10 min. Forty microliters of postnuclear supernatant (PNS) was mixed with 5 ml of Folch extract (chloroformmethanol, 2 : 1), and the mixture was incubated for 10 min at 37°C with shaking. After the mixture was centrifuged at 3000ϫg for 10 min, 3 ml of the supernatant was evaporated dry by boiling at 100°C, and then dissolved in 200 ml of isopropyl alcohol containing 1% Triton-X-100. The cholesterol content of the solution or serum (20 ml) was determined using the Cholesterol E-test Wako (optical density (OD) 600 nm). Isolation of HDL and VLDL/LDL Fractions from SerumThe HDL and VLDL/LD...

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Chronic Production of Peroxynitrite in the Vascular Wall Impairs Vasorelaxation Function in SHR/NDmcr-cp Rats, an Animal Model of Metabolic Syndrome

Cited by 32 publications

References 40 publications

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Irbesartan Prevents Metabolic Syndrome in Rats via Activation of Peroxisome Proliferator-Activated Receptor γ

Comparison of Receptors and Enzymes Regulating Cholesterol Levels in Liver between SHR/NDmcr-cp Rats and Normotensive Wistar Kyoto Rats at Ten Weeks of Age

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