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Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats.

ABSTRACT: Mild hyperhomocysteinemia (HHcy, clinically defined as less than 30 ?mol/L) is an independent cardiovascular disease (CVD) risk factor, and is associated with many complications during pregnancy, such as preeclampsia (PE). The aim of this study was to assess the effect of long-term mild HHcy on cardiac metabolic function of multiparous rats. Female rats were mated 3 to 4 times and were fed with methionine in drinking water to increase plasma Hcy (2.9 ± 0.3 to 10.5 ± 2.3 ?mol/L) until termination. This caused significant increase of heart weight/body weight (0.24 ± 0.01 to 0.27 ± 0.01 g/100 g) and left ventricle weight (0.69 ± 0.03 to 0.78 ± 0.01 g). Superoxide production was increased by 2.5-fold in HHcy hearts using lucigenin chemiluminescence. The ability of bradykinin and carbachol to regulate myocardial oxygen consumption (MVO2) in vitro was impaired by 59% and 66% in HHcy heart, and it was restored by ascorbic acid (AA), tempol, or apocynin (Apo). Protein expression of p22(phox) subunit of NAD(P)H oxidase was increased by 2.6-fold, but there were no changes in other NAD(P)H oxidase subunits, NOSs or SODs. Microarray revealed 1518 genes to be differentially regulated (P < 0.05). The mRNA level of NAD(P)H oxidase subunits, NOSs or SODs remained unchanged. In conclusion, long-term mild HHcy increases cardiac superoxide mainly through regulation of p22(phox) component of the NAD(P)H oxidase and impairs the ability of NO to regulate MVO2 in heart of multiparous mothers.

SUBMITTER: Song S

PROVIDER: S-EPMC4463811 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats.

Song Su S Kertowidjojo Elizabeth E Ojaimi Caroline C Martin-Fernandez Beatriz B Kandhi Sharath S Wolin Michael M Hintze Thomas H TH

Physiological reports 20150501 5

Mild hyperhomocysteinemia (HHcy, clinically defined as less than 30 μmol/L) is an independent cardiovascular disease (CVD) risk factor, and is associated with many complications during pregnancy, such as preeclampsia (PE). The aim of this study was to assess the effect of long-term mild HHcy on cardiac metabolic function of multiparous rats. Female rats were mated 3 to 4 times and were fed with methionine in drinking water to increase plasma Hcy (2.9 ± 0.3 to 10.5 ± 2.3 μmol/L) until termination ...[more]

PMID: 26009634

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Project description:Hyperhomocysteinemia has long been associated with atherosclerosis and thrombosis and is an independent risk factor for cardiovascular disease. Its causes include both genetic and environmental factors. Although homocysteine is produced in every cell as an intermediate of the methionine cycle, the liver contributes the major portion found in circulation, and fatty liver is a common finding in homocystinuric patients. To understand the spectrum of proteins and associated pathways affected by hyperhomocysteinemia, we analyzed the mouse liver proteome of gene-induced (cystathionine beta-synthase (CBS)) and diet-induced (high methionine) hyperhomocysteinemic mice using two-dimensional difference gel electrophoresis and Ingenuity Pathway Analysis. Nine proteins were identified whose expression was significantly changed by 2-fold (p < or = 0.05) as a result of genotype, 27 proteins were changed as a result of diet, and 14 proteins were changed in response to genotype and diet. Importantly, three enzymes of the methionine cycle were up-regulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine N-methyltransferase and betaine-homocysteine methyltransferase only increased in response to diet. The antioxidant proteins peroxiredoxins 1 and 2 increased in wild-type mice fed the high methionine diet but not in the CBS mutants, suggesting a dysregulation in the antioxidant capacity of those animals. Furthermore, thioredoxin 1 decreased in both wild-type and CBS mutants on the diet but not in the mutants fed a control diet. Several urea cycle proteins increased in both diet groups; however, arginase 1 decreased in the CBS(+/-) mice fed the control diet. Pathway analysis identified the retinoid X receptor signaling pathway as the top ranked network associated with the CBS(+/-) genotype, whereas xenobiotic metabolism and the NRF2-mediated oxidative stress response were associated with the high methionine diet. Our results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense.

Project description:BackgroundConsumption of added sugars has been considered a worldwide public health concern by its association with metabolic syndrome and its comorbidities. Meanwhile, current studies have suggested high-protein diets to promote weight loss and improved metabolic outcomes. Thus, this study aimed to investigate the effects of long-term high-protein diet (HPD, 34.3% protein) intake on high-sucrose-fed rats.MethodsWeaned male Wistar rats were randomized into two groups: rats fed a standard chow (CT/CT, 10% sucrose) or rats fed a high-sucrose diet (HSD, 25% sucrose) for a 20-week observational period. Subsequently, HS/HS animals were randomized into 3 new groups: rats maintained on HSD diet (HS/HS); rats submitted to HSD replacement by standard chow (HS/CT); and those with HSD replaced by HPD (HS/HP). All groups were followed up for 12 weeks during which we investigated the effects of HPD on body weight, energy intake, obesity development, glicemic/lipid profile, glucose tolerance, insulin resistance, tissue weight (adipose tissue, liver and skeletal muscles), lipolytic activity, liver lipoperoxidation and histology, as well as serum markers of hepatic function.ResultsPost-weaning exposure to HSD led to metabolic syndrome phenotype at adulthood, herein characterized by central obesity, glucose intolerance, dyslipidaemia and insulin resistance. Only HPD feeding was able to revert weight gain and adipose tissue accumulation, as well as restore adipose tissue lipolytic response to sympathetic stimulus. On the other hand, either HPD or withdrawal from HSD promoted very similar metabolic outcomes upon 12-week nutritional intervention. HS/HP and HS/CT rats showed reduced fasting serum levels of glucose, triacylglycerol and total cholesterol, which were correlated with the improvement of peripheral insulin sensitivity, as inferred from kITT and TyG Index values. Both nutritional interventions restored liver morphofunctional patterns, but only HPD restored lipid peroxidation.ConclusionsOur data showed that 12-week intake of an isocaloric moderately high-protein diet consistently restored high-sucrose-induced central adiposity and obesity in addition to the attenuation of other important metabolic outcomes, such as improvement of glucolipid homeostasis associated to increased insulin sensitivity and reversal of hepatic steatosis. On the other hand, simple withdrawal from high-sucrose consumption also promoted the abovementioned metabolic outcomes with no impact on body weight.

Dataset Information

Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats.

Publications

Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats.

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