Winter-dormant shoot apical meristem in poplar trees shows environmental epigenetic memory.

Trees have a long lifespan and must continually adapt to environmental pressures, notably in the context of climate change. Epigenetic mechanisms are doubtless involved in phenotypic plasticity and in stress memory; however, little evidence of the role of epigenetic processes is available for trees growing in fields. Here, we analyzed the possible involvement of epigenetic mechanisms in the winter-dormant shoot apical meristem of Populus × euramericana clones in memory of the growing conditions faced during the vegetative period. We aimed to estimate the range of genetic and environmentally induced variations in global DNA methylation and to evaluate their correlation with changes in biomass production, identify differentially methylated regions (DMRs), and characterize common DMRs between experiments. We showed that the variations in global DNA methylation between conditions were genotype dependent and correlated with biomass production capacity. Microarray chip analysis allowed detection of DMRs 6 months after the stressful summer period. The 161 DMRs identified as common to three independent experiments most notably targeted abiotic stress and developmental response genes. Results are consistent with a winter-dormant shoot apical meristem epigenetic memory of stressful environmental conditions that occurred during the preceding summer period. This memory may facilitate tree acclimation.

Endothelial dysfunction in rat adjuvant-induced arthritis: up-regulation of the vascular arginase pathway.

OBJECTIVE: To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA. METHODS: We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N(ω)-hydroxy-nor-L-arginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting. RESULTS: ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity. CONCLUSION: Our results are consistent with the notion that arginase up-regulation plays a role in AIA-associated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

Influence of the consumption pattern of magnesium from magnesium-rich mineral water on magnesium bioavailability.

It is generally considered that the absorption of Mg is inversely related to the ingested dose. The objective of the present study was to determine if the mode of administration (bolus v. consumption throughout the day) could influence Mg bioavailability from Mg-rich natural mineral water comparing the same nutritional Mg amount (126 mg). Using a 2 d cross-over design, twelve healthy men were asked to drink 1·5 litres Mg-rich mineral water either as 2 × 750 ml or 7 × 212 ml throughout the day. Two stable isotopes ((25)Mg and (26)Mg) were used to label the water in order to distinguish both regimens. Fractional apparent Mg absorption was determined by faecal monitoring and Mg retention was determined by measuring urinary excretion of Mg isotopes. Higher Mg absorption (50·7 (SD 12·7) v. 32·4 (SD 8·1) %; P = 0·0007) and retention (47·5 (SD 12·9) v. 29·0 (SD 7·5) %; P = 0·0008) from Mg-rich mineral water were observed when it was consumed in seven servings compared with larger servings. Thus, regular water consumption throughout the day is an effective way to increase Mg bioavailability from Mg-rich mineral water.

Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio.

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10(-4) mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10(-5) mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm(2) (1 dyn = 10(-5) N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.

Long-term swimming exercise does not modulate the Akt-dependent endothelial nitric oxide synthase phosphorylation in healthy mice.

Molecular mechanisms by which exercise exerts cardiovascular benefits are poorly understood. Exercise-induced increase of endothelial NO synthase (eNOS) phosphorylation through the protein kinase Akt has been shown to be a key mechanism underlying the beneficial effect of exercise in coronary artery disease patients. We examined whether this protective pathway might also be activated in long-term-exercised healthy mice. C57BL/6 wild-type mice swam for 24 weeks. A group of sedentary animals were used as controls. Aortic levels of total protein kinase Akt (protein kinase B), phosphorylated Akt at ser473 (p-Akt), total eNOS, phosphorylated eNOS at Ser1177 (p-eNOS), and PECAM-1 (platelet endothelial cell adhesion molecule-1) were assessed by Western blotting. Protein expressions of Akt, p-Akt, eNOS, p-eNOS, and PECAM-1 were not modulated by 24 weeks of exercise. The Akt-dependent eNOS phosphorylation did not seem to be a primary molecular adaptation in response to long-term exercise in healthy mice.

Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin.

Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

Effects of cadmium on cardiac metallothionein induction and ischemia-reperfusion injury in rats.

Myocardial ischemia-reperfusion injury is associated with an imbalance between the formation and the scavenging of reactive oxygen species. In this context, the protective role of the antioxidant metallothionein, a thiol-rich protein that is induced in different organs in response to heavy metals and oxidative conditions, has mainly been investigated in metallothionein-knockout mice or metallothionein-overexpressing mice. The aim of this study was to evaluate whether the administration of cadmium has a protective effect against cardiac ischemia-reperfusion injury and whether this is associated with induction of in vivo cardiac metallothionein. Forty-eight hours after an injection of 0, 1, or 2 mg/kg cadmium, isolated perfused rat hearts were submitted to 30 min of total global ischemia and 30 min of reperfusion. The ischemia-reperfusion sequence was associated with a significant decrease in cardiac metallothionein levels. Pretreatment with cadmium at a dose of 2 mg/kg (i) prevented this decrease and (ii) improved the postischemic recuperation of the coronary flow, the ventricular developed pressure, and therefore, the global postischemic functional recovery. These results showed that pretreatment of rats with 2 mg/kg cadmium induced cardioprotection against ischemia-reperfusion injuries, perhaps through an in vivo metallothionein induction that may be related to a metal activation of antioxidant systems.

A long-term moderate magnesium-deficient diet aggravates cardiovascular risks associated with aging and increases mortality in rats.

OBJECTIVE: The present study aimed to show whether long-term moderate magnesium (Mg)-deficient (150 mg/kg) and Mg-supplemented (3200 mg/kg) diets (versus control diet: 800 mg/kg), modified the occurrence of cardiovascular risk induced by aging in the rat. METHODS: Cardiovascular and arterial functions were determined by a systemic hemodynamic study and by ex vivo measurements of vasoconstriction and endothelium dependent-vasorelaxation. Arterial wall structure was determined using pressure myograph chamber and histomorphometric methods. RESULTS: The main changes observed in old rats (96 weeks old) fed a control diet, in comparison to adult rats (16 weeks old) were increased pulse pressure, a loss of aortic endothelium-dependent relaxation, increased aortic wall thickness and a decrease of the aortic wall elastin/collagen ratio. Long-term moderate Mg deficiency progressively increased systolic blood pressure. Intra-arterial pulse pressure was higher in Mg-deficient old rats than in age-matched control rats. Histological examination showed that Mg deficiency increased the age-induced deleterious effects on composition and structure of aorta (media thickness, increased collagen content and reduction in the elastin/collagen ratio), which lead to large artery rigidity. Hypertension and increased pulse pressure may have contributed to the increase in the mortality rate observed in the hypertensive Mg-deficient group. Although the long-term Mg-supplemented diet lowered blood pressure and decreased the mortality rate, it had no significant effect on aortic wall thickening and stiffening. CONCLUSION: It is suggested that a long-term and moderate Mg-deficient diet increases age-induced arterial thickness and stiffness in rats, and thus increases the cardiovascular risks incurred by aging.

Treatment with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat.

OBJECTIVE: High vascular arginase activity and subsequent reduction in vascular nitric oxide production were recently reported in animal models of hypertension. The present study investigated the effects of in-vivo arginase inhibition on blood pressure and vascular function in adult spontaneously hypertensive rats. METHODS: Ten-week-old spontaneously hypertensive rats and normotensive age-matched Wistar-Kyoto rats were treated with or without the selective arginase inhibitor N-hydroxy-nor-L-arginine for 3 weeks (10 or 40 mg/kg per day, intraperitoneally). Systolic blood pressure and cardiac rate were measured before and during treatment. Flow and pressure-dependent reactivity as well as remodeling of mesenteric arteries, acetylcholine-dependent vasodilation of aortic rings, cardiac hypertrophy, arginase activity and nitric oxide production were investigated in 13-week-old spontaneously hypertensive rats. RESULTS: In spontaneously hypertensive rats, N-hydroxy-nor-L-arginine treatment decreased arginase activity (30-40%), reduced blood pressure ( approximately 35 mmHg) and improved the reactivity of mesenteric vessels. However, vascular and cardiac remodeling was not different between treated and untreated spontaneously hypertensive rats. In Wistar-Kyoto rats, N-hydroxy-nor-L-arginine did not affect blood pressure. Finally, arginase inhibition was associated with increased nitric oxide production. Consistent with this, the response of aortic rings to acetylcholine was fully restored by N-hydroxy-nor-L-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the effect of N-hydroxy-nor-L-arginine on flow-dependent vasodilation. CONCLUSION: Pharmacological inhibition of arginase in adult spontaneously hypertensive rats decreases blood pressure and improves the reactivity of resistance vessels. These data represent in-vivo argument in favor of selective arginase inhibition as a new therapeutic strategy against hypertension.

Vascular function of MGH and MGL mice, two strains which differ by a genetic variation of magnesium metabolism.

Mg deficiency is considered as a risk factor of cardiovascular disorders like hypertension and atherosclerosis. MGH and MGL mice, selected for high and low Mg status, are animal models which present variations of Mg metabolism of genetic origin. The cardiovascular functions of these mice have never been studied. In this study, the arterial blood pressure of MGH and MGL strains was measured by plethysmography. Morphology and reactivity to vasoconstrictor agents were also investigated by a pressurized and perfused system in mesenteric resistance artery. It is shown that: (1) MGH mice presented a higher plasma Mg concentration than MGL; (2) arterial blood pressure and heart rates were similar between the two groups; (3) media thickness, media cross-sectional area, and internal and external diameters were smaller in pressurized mesenteric resistance arteries from MGH mice than in those from MGL mice; (4) the vasoconstriction induced by vasopressin (but not norepinephrine) was higher in the mesenteric arteries from MGH mice than in those from MGL ones. In summary, MGH mice as compared to MGL mice present differences in arterial geometry and higher reactivity to vasopressin without repercussions on arterial blood pressure. The real repercussion of these observations on the cardiovascular system of the MGH and MGL models is at present unknown. More experiments are needed to clarify the influence of differences in Mg metabolism of genetic origin on cardiovascular function.

Effects of long-term dietary intake of magnesium on oxidative stress, apoptosis and ageing in rat liver.

In the present study, we investigated the effect of long-term dietary Mg intake on the rate of oxidative stress, apoptosis and ageing in rat livers. To address this issue, rats were fed diets containing either a moderately deficient (0.15 g Mg/kg diet), a standard (0.8 g Mg/kg diet) or a high (3.2 g Mg/kg diet) Mg dose for two years. It is noteworthy that a higher percentage of animal mortality was observed in the lowest Mg diet, as compared to the other groups. Oxidative stress and antioxidant status were evaluated by measuring different enzyme activities, among which glutathione peroxidase activity was significantly reduced when Mg content was decreased in the diet. Moreover, we obtained an activation of caspase-3 and a higher lipid peroxidation in the Mg-deficient group, as compared to the Mg standard group, while no changes in Mg-supplemented group were observed, in accordance with our previously published data in primary cultures of rat hepatocytes (Martin et al., J Nutr 2003). Telomere shortening was measured in rat livers, as a marker of ageing. We found that telomere length was decreased in old animals, as compared to young animals confirming that telomere shortening correlated well with ageing events. Moreover, in old animals, we obtained a decrease of telomere length in the Mg-deficient group, as compared to the other groups. Taken together, our results show that a long-term chronic Mg deficiency led to oxidative stress, apoptosis and an acceleration of ageing in rat livers.

New insights into the vascular mechanisms underlying the beneficial effect of swimming training on the endothelial vasodilator function in apolipoprotein E-deficient mice.

The antiatherogenic role of exercise is poorly understood. We examined the swimming exercise-induced vascular mechanisms which enhance the endothelial vasodilator function in apoE(-/-) mice. Male apoE(-/-) mice treated for 9 weeks with a lipid-rich diet were divided into two groups: the exercise group (apoE(-/-) X), which underwent a 9-week swimming protocol (50 min/day; 5days/week) and the sedentary group (apoE(-/-) S). C57BL/6 mice were used as the control group. Atherosclerotic lesions in the aortic roots were significantly reduced in apoE(-/-) X compared to apoE(-/-) S. Relaxation to acetylcholine was improved in apoE(-/-) X as compared to apoE(-/-) S and control mice with E(max) and pD(2) values significantly higher. pD(2) values in response to papaverine were higher in apoE(-/-) X than in the other groups. Relaxation in response to A23187 and DEA-NONOate were similar. These findings suggest that swimming training may increase the sensitivity of relaxation to acetylcholine, which in turn activates acetylcholine-mediated signaling pathways leading to increased NO bioactivity. Swimming may also prolong the signaling actions of NO by stimulating the sensitivity of vascular smooth muscle cells to cyclic nucleotides. These appear to be the key mechanisms underlying the improvement of the NO-cGMP pathway in exercised apoE(-/-) mice.

Effects of isometric strength training followed by no exercise and Humulus lupulus L-enriched diet on bone metabolism in old female rats.

We investigated in female rats the effects on bone metabolism of a prolonged no-training period, subsequent to an isometric exercise program, performed during young adulthood and those of a long-term consumption of Humulus lupulus L-enriched diet (genistein 1.92 and daidzein 1.24 mg/kg diet) combined or not with isometric training. Forty-eight rats (4 weeks old) were randomly divided into 4 groups: trained (C-Tr) or nontrained rats (C-NTr) fed with control diet and trained (H-Tr) or nontrained rats (H-NTr) fed with Humulus lupulus L-enriched diet. The diets lasted 100 weeks. Training was followed over a 25-week period. Bone parameters were measured at week 100. Our results showed that no significant difference was observed among the 4 groups in uterine relative weight, calcium (Ca) intake, fecal Ca, urinary Ca excretion, net Ca absorption, plasma Ca, and bone Ca content. Calcium balance was significantly enhanced in H-NTr rats in comparison with C-NTr and C-Tr rats. Isometric strength training led to a significant increase in total bone mineral density (BMD), diaphyseal BMD, and osteocalcin-deoxypyridinoline ratio in C-Tr rats compared with the other groups. The main findings of the present study indicate that in female rats, a 25-week isometric strength training performed during young adulthood followed by a prolonged no-training period increases BMD values and osteocalcin-deoxypyridinoline ratio, whereas long-term consumption of Humulus lupulus L-enriched diet does not improve bone parameters. It suggests that bone gains induced by exercise do not decrease immediately after cessation of training and also confirms the importance of the practice of physical activity during puberty and young adulthood to maximize the achieved peak bone density.

Time course of vascular arginase expression and activity in spontaneously hypertensive rats.

There is growing evidence that vascular arginase plays a role in pathophysiology of vascular diseases. We recently reported high arginase activity/expression in young adult hypertensive spontaneously hypertensive rats (SHR). The aim of the present study was to characterize the time course of arginase pathway abnormalities in SHR and to explore the contributing role of hemodynamics and inflammation. Experiments were conducted on 5, 10, 19 and 26-week-old SHR and their age-matched control Wistar Kyoto (WKY) rats. Arginase activity as well as expression of arginase I, arginase II, endothelial and inducible NOS were determined in aortic tissue extracts. Levels of L-arginine, NO catabolites and IL-6 (a marker of inflammation) were measured in plasma. Arginase activity/expression was also measured in 10-week-old SHR previously treated with hydralazine (20 mg/kg/day, per os, for 5 weeks). As compared to WKY, SHR exhibited high vascular arginase I and II expression from prehypertensive to established stages of hypertension. However, a mismatch between expression and activity was observed at the prehypertensive stage. Arginase expression was not related either to plasma IL-6 levels or to expression of NOS. Prevention of hypertension by hydralazine significantly blunted arginase upregulation and restored arginase activity. Importantly, arginase activity and blood pressure (BP) correlated in SHR. In conclusion, our results demonstrate that arginase upregulation precedes blood pressure rising and identify elevated blood pressure as a contributing factor of arginase dysregulation in genetic hypertension. They also demonstrated a close relationship between arginase activity and BP, thus making arginase a promising target for antihypertensive therapy.

Immobilization of arginase and its application in an enzymatic chromatographic column: thermodynamic studies of nor-NOHA/arginase binding and role of the reactive histidine residue.

A biochromatographic approach is developed to measure for the first time changes in enthalpy, heat capacity change and protonation for the binding of nor-NOHA to arginase in a wide temperature range. For this, the arginase enzyme was immobilized on a chromatographic support. It was established that this novel arginase column was stable during an extended period of time. The affinity of nor-NOHA to arginase is high and changes slightly with the pH, because the number of protons linked to binding is low. The determination of the enthalpy change at different pH values suggested that the protonated group in the nor-NOHA-arginase complex exhibits a heat protonation of approximately -33 kJ/mol. This value agrees with the protonation of an imidazole group. Our result confirmed that active-site residue Hist 141 is protonated as imidazolium cation. Hist 141 can function as a general acid to protonate the leaving amino group of L-ornithine during catalysis. The thermodynamic data showed that nor-NOHA-arginase binding, for low temperature (<15 degrees C), is enthalpically unfavourable and being dominated by a positive entropy change. This result suggests that dehydration at the binding interface and charge-charge interactions contribute to the nor-NOHA-arginase complex formation. The temperature dependence of the free energy of binding is weak because of the enthalpy-entropy compensation caused by a large heat capacity change, DeltaC(p)=-2.43 kJ/mol/K, of arginase. Above 15 degrees C, the thermodynamic data DeltaH and DeltaS became negative due to van der Waals interactions and hydrogen bonding which are engaged at the complex interface confirming strong enzyme-inhibitor hydrogen bond networks. As well, by the use of these thermodynamic data and known correlations it was clearly demonstrated that the binding of nor-NOHA to arginase produces slight conformational changes in the vicinity of the active site. Our work indicated that our biochromatographic approach could soon become very attractive for studying other enzyme-ligand binding.

Effects of long-term dietary intake of magnesium on rat liver transcriptome.

In the present study we investigated the effect of a two-year treatment period with a diet containing 3.2g, 0.8 g and 0.15 g Mg/kg, on the rat liver transcriptome. At the end of the study, a treatment-dependent decrease in plasmatic Mg concentration was found (0.86 +/- 0.02 mmol/L, 0.70 +/- 0.02 mmol/L and 0.52 +/- 0.03 mmol/L for groups receiving 3.2g, 0.8 g and 0.15 g Mg/kg diet, respectively). No significant treatment-related effect on body and liver weights was observed, however a dietary Mg intake-dependent increase in mortality rate occurred in animals (11%, 25% and 38% death of animals). Mg content in the diet affected gene expression in rat livers, as assessed by rat specific DNA microarrays. We identified 11 genes up-regulated and 39 genes down-regulated by at least two-fold by a decrease in Mg content and grouped them within five functional pathways: metabolism 20%, cytoarchitecture (connective tissue/cell adhesion/cytoskeleton) 12%, channels/ transporters 20%, turn-over (nucleic acid and protein) 16%, and homeostasis (stress/DNA damage/apoptosis/ageing) 32%. The results of the present study confirm the pleiotropic effects of Mg and provide further evidence that a Mg decrease in the diet may be considered as a promoting factor for pathologies, especially in the liver, during ageing.

Magnesium deficiency affects HNF1ß expression in rat liver in vivo and in vitro.

Hepatocyte nuclear factor 1ß (HNF1ß) is a transcription factor that is involved in embryonic development and tissue-specific gene expression in several organs, including the kidney and the liver. HNF1ß mutations are associated with hypomagnesemia and renal magnesium wasting; however, to date, the exact molecular mechanism involved in this regulation is unclear. Furthermore, it is not known whether the Mg concentration could per se participate to this regulation by modifying HNF1ß expression. We have studied in rats the effects of a 6-week diet with deficient or supplemented Mg concentrations compared to a diet with a standard Mg concentration on HNF1ß protein expression. HNF1ß expression was increased in the Mg-deficient group as compared to the other groups in the liver but not in the kidney. No changes in tissue Mg level were obtained in both organs. By contrast, a significant correlation between plasma Mg concentration and HNF1ß level in the rat liver was evidenced. In rat hepatocyte cultures exposed for 72h to various extracellular Mg concentrations, HNF1ß expression was modified after 72h of treatment of the hepatocytes with the lowest Mg concentrations as compared to the other Mg conditions. Moreover, these changes were correlated with extracellular but not intracellular Mg concentrations. In conclusion, HNF1ß expression is modified by the extracellular Mg concentration in the liver, both in vivo and in vitro, suggesting regulations with membrane events in hepatocytes.

Running Exercise and Angiotensin II Type I Receptor Blocker Telmisartan Are Equally Effective in Preventing Angiotensin II-Mediated Vulnerable Atherosclerotic Lesions.

INTRODUCTION: The present study was conducted to directly compare the efficacy of running exercise and telmisartan treatment on angiotensin (Ang) II-mediated atherosclerosis and plaque vulnerability. MATERIALS AND METHODS: Apolipoprotein E-deficient (ApoE-/-) mice with Ang II-mediated atherosclerosis (2-kidney, 1-clip [2K1C] renovascular hypertension model) were randomized into 3 groups: treadmill running exercise (RUN), telmisartan treatment (TEL), and sedentary untreated controls (SED) for 5 weeks. Atherosclerosis was assessed using histological and immunohistochemical analyses. Gene expression was determined by real-time reverse transcription polymerase chain reaction. RESULTS: TEL but not RUN mice significantly decreased (50%) atherosclerotic lesion size compared to SED. RUN and TEL promoted plaque stabilization to a similar degree in ApoE-/- 2K1C mice. However, plaque composition and vascular inflammatory markers were differently affected: RUN decreased plaque macrophage infiltration (35%), whereas TEL reduced lipid core size (88%); RUN significantly increased aortic peroxisome proliferator-activated receptor (PPAR)-α, -δ, and -γ expression, whereas TEL significantly modulated T-helper 1/T-helper 2 (Th1/Th2) aortic response toward an anti-inflammatory state (decreased aortic interleukin [IL] 2 to IL-10 and IL-2 to IL-13 expression ratios). Plaque smooth muscle cell content was similarly increased (128% and 141%, respectively). Aortic AT1 and AT2 receptor expression as well as aortic CD11c/CD206 and IL-1ß/IL-1ra expression ratios were not significantly modulated by either RUN or TEL. CONCLUSION: Running exercise and telmisartan treatment are equally effective in preventing Ang II-mediated plaque vulnerability but through distinct cellular and molecular mechanisms. Our findings further support the use of exercise training and selective AT1 receptor blocker therapies for atherosclerotic cardiovascular disease prevention.

Long-term moderate magnesium-deficient diet shows relationships between blood pressure, inflammation and oxidant stress defense in aging rats.

Epidemiological and experimental studies have indicated a relationship among aging, dietary Mg, inflammatory stress, and cardiovascular disease. Our aim in the present study was to investigate possible links between dietary Mg, oxidant stress parameters, and inflammatory status with aging in rats. We designed a long-term study in which rats were fed for 22 months with moderately deficient (150 mg/kg), standard (800 mg/kg), or supplemented (3200 mg/kg) Mg diets. Comparisons were made with young rats fed with the same diets for 1 month. Compared to the standard and supplemented diets, the Mg-deficient diet significantly increased blood pressure, plasma interleukin-6, fibrinogen, and erythrocyte lysophosphatidylcholine, particularly in aging rats, it decreased plasma albumin. The impairment of redox status was indicated by increases in plasma thiobarbituric acid reactive substances and oxysterols and an increased blood susceptibility to in vitro free-radical-induced hemolysis. We concluded that Mg deficiency induced a chronic impairment of redox status associated with inflammation which could significantly contribute to increased oxidized lipids and promote hypertension and vascular disorders with aging. Extrapolating to the human situation and given that Mg deficiency has been reported to be surprisingly common, particularly in the elderly, Mg supplementation might be useful as an adjuvant therapy in preventing cardiovascular disease.

Dietary magnesium intake alters age-related changes in rat adipose tissue cellularity.

Obesity and related metabolic diseases are associated with increased risk of cardiovascular disease. We have previously shown the beneficial effects of dietary magnesium (Mg) supplementation on cardiovascular disease in rats. Therefore, we aimed to examine the effect of an Mg-deficient or supplemented diet on adipose tissue cellularity changes during aging, and on blood pressure (BP), in rats. Male rats received for one (young adult) or 22 months (old), an Mg-deficient (Def) (150 mg/kg), standard (Std) (800 mg/kg) or Mg-supplemented (Sup) (3200 mg/kg) diet. Adipose tissue development and cellularity, BP and leptinemia were evaluated. In rats fed a standard diet, the large increase in adipose tissue weight observed during aging was related to an increase in both size and number of adipocytes. In young adult rats, although adiposity was unchanged, Mg supplementation resulted in a shift of the frequency distribution of adipocytes toward greater sizes, adipose cell weight increasing by 62%. Mg deficiency did not modify adipocyte size, but increased their number (30% more than for the standard or Sup-diet). In old rats, the Def-diet led to relative adipocyte hypotrophy, which was counterbalanced by an increase in the number of adipocyte. Conversely, adipocyte size and number were similar in the Sup-diet and standard diet-fed rats. BP was modified in old rats according to dietary Mg, whereas it remained unchanged young adult rats regardless of the diet received. This study suggests that Mg intake may affect age-related changes in rat adipose tissue lipid storage capacity.