Biomedical subjects

Zhenmin Ni

Publications and source records attributed to Zhenmin Ni.

10 recordsLinked to original sources

PubMed2006

Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence.

Mitochondria are the major source of superoxide (O(2)(-)) in the aerobic organisms. O(2)(-) produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2(-/-)) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2(+/-)) show evidence of O(2)(-)-induced mitochondrial damage resembling cell senescence. Since earlier studies have provided compelling evidence for the role of oxidative stress and tubulointerstitial inflammation in the pathogenesis of hypertension, we tested the hypothesis that partial SOD2 deficiency may result in hypertension. Wild-type (SOD2(+/+)) and partial SOD2-deficient (SOD2(+/-)) mice had similar blood pressures at 6-7 mo of age, but at 2 yr SOD2(+/-) mice had higher blood pressure. Oxidative stress, renal interstitial T-cell and macrophage infiltration, tubular damage, and glomerular sclerosis were all significantly increased in 2-yr-old SOD2(+/-) mice. High-salt diet induced hypertension in 6-mo-old SOD2-deficient mice but not in wild-type mice. In conclusion, partial SOD2 deficiency results in oxidative stress and renal interstitial inflammation, changes compatible with accelerated renal senescence and salt-sensitive hypertension. These findings are consistent with the pattern described in numerous other models of salt-sensitive hypertension and resemble that commonly seen in elderly humans.

Animals↗

PubMed2006

Low albumin levels increase endothelial NO production and decrease vascular NO sensitivity.

BACKGROUND: Hypoalbuminaemia is associated with increased risk of cardiovascular disease. It is unclear whether endothelial dysfunction is a direct result of low albumin or whether it is caused by factors like chronic inflammation or dyslipidaemia. In this study, the effect of low albumin concentrations on endothelial nitric oxide synthase (eNOS)-dependent NO production was determined in vitro and ex vivo. METHODS: eNOS activity, assessed by arginine-citrulline conversion, and NO production, determined by 4,5-diaminofluorescein diacetate, electron paramagnetic resonance and Griess colorimetry, were measured in cultured endothelial cells expressing high levels of eNOS (bEnd.3) after exposure to albumin concentrations ranging from 0.5 mmol/l (33 g/l) to 0 mmol/l. Analbuminaemic and control rat plasma NO metabolites and aortic eNOS protein mass were determined, and aortic endothelium-independent and endothelium-dependent vasodilator tone were measured ex vivo under albumin-free conditions. RESULTS: In vitro, eNOS activity was significantly increased in the absence of albumin (75 +/- 2 vs 26 +/- 6 pmol/min/mg protein; P < 0.01). Low albumin levels consistently increased NO production in endothelial cells. Plasma NO metabolites were increased (18.2 +/- 1.9 vs 12.5 +/- 0.8 micromol/l; P < 0.05) and endothelium-independent relaxation was markedly blunted in analbuminaemic rats, resulting in a considerably higher ED50 (80 +/- 2 vs 1.1 +/- 0.2 nmol/l, P < 0.01), while endothelium-dependent dilatation was slightly, but significantly, increased. Aortic eNOS protein mass was not affected. This implies that in vivo hypoalbuminaemia reduces vascular NO sensitivity. CONCLUSION: We show that low albumin as such seems to enhance, rather than diminish, eNOS-mediated endothelial NO production.

Albumins↗

PubMed2004

Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cells.

BACKGROUND: Chronic lead exposure causes hypertension and cardiovascular disease, which are associated with, and, in part, due to oxidative stress. While occurrence of oxidative stress in lead-exposed animals and cultured endothelial cells has been well-established, direct and specific evidence on the type of the reactive oxygen species (ROS) produced by lead-exposed vascular cells is lacking and was investigated. METHODS: Human coronary endothelial (EC) and vascular smooth muscle cells (VSMC) were incubated in appropriate culture media in the presence of either 1 ppm or 10 ppm lead acetate or sodium acetate (control) for 1 to 30 minutes or 60 hours. Productions of superoxide and hydrogen peroxide in the cell populations were determined by flow cytometry using hydroethidine and dihydrorhodamine, respectively. Data from a minimum of 10,000 cells were collected and analyzed using Cell Quest software. In addition, Cu Zn superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), and NAD(P)H oxidase (gp91phox) were measured. RESULTS: Short-term lead exposure resulted in a significant rise in both superoxide and hydrogen peroxide production by both EC and VSMC. After long-term exposure, detectable superoxide levels fell to near normal level, while hydrogen peroxide production remained high. This was associated with up-regulations of gp91phox, elevation of superoxide dismutase, reduction of VSMC catalase, and no change in GPX levels. Together, these events can account for the observed decline in superoxide and the rise in hydrogen peroxide following long-term lead exposure. CONCLUSION: Lead exposure promotes generation of superoxide and hydrogen peroxide in human EC and VSMC. This phenomenon can potentially contribute to the pathogenesis of the lead-associated hypertension and cardiovascular disease, and points to the potential benefit of lowering lead burden in the exposed populations.

Catalase↗

PubMed2003

Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria.

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.

Animals↗

PubMed2003

Blood pressure response to hypoxia: role of nitric oxide synthase.

BACKGROUND: Chronic exposure to hypobaric hypoxia has been shown to increase arterial pressure in genetically normal rats. The associated increase in blood pressure is unrelated to the hypoxia-induced erythrocytosis and persists indefinitely after restoration of normoxia. It is accompanied by a marked reduction in urinary excretion of nitric oxide metabolites (NOx) and is ameliorated by L-arginine supplementation. In view of the latter observations, we hypothesized that hypoxia-induced hypertension may be associated with downregulation of NO synthase (NOS). METHODS: Male Sprague Dawley rats were randomized to the hypoxic and control groups. Rats assigned to the hypoxic group were placed in chambers with air pressure maintained at 390 mm Hg. Animals assigned to the control group were kept in the chamber at 760 mm Hg air pressure. Animals were kept in their respective conditions for up to 21 days. Group of animals were tested at days 2, 3, 7, and 21. RESULTS: The hypoxic group exhibited a steady increase in arterial pressure beginning at day 3. This was accompanied by a transient increase followed by a significant decline in kidney NOS-I, NOS-II, and NOS-III abundance. A similar biphasic change was observed with NOS-II and NOS-III in the cardiac and vascular tissues. The changes in NOS abundance in the given tissues were associated with parallel changes in nitrotyrosine abundance, which reflects local NO production. The latter finding provides functional evidence for the changes observed in NOS abundance. CONCLUSIONS: Chronic hypoxia-induced hypertension in rats is associated with marked downregulation of NOS isotypes, which can, in part, account for the previously reported L-arginine-responsive hypertension in this model.

Air Pressure↗

PubMed2002

Reversal of biochemical and behavioral parameters of brain aging by melatonin and acetyl L-carnitine.

The potential utility of dietary supplementation in order to prevent some of the oxidative and inflammatory changes occurring in the brain with age, has been studied. The cerebral cortex of 27-month-old male B6C3F1 mice had elevated levels of nitric oxide synthase 1 (EC 1.14.13.39) (nNOS) and peptide nitrotyrosine relative to cortices of younger (4-month-old) animals. After 25-month-old mice received basal diet together with 300 mg/l acetyl L-carnitine in the drinking water for 8 weeks, these levels were fully restored to those found in younger animals. A partial restoration was found when old animals received basal diet supplemented with 200 ppm melatonin in the diet. Levels of mRNA (messenger RNA) for nNOS were unchanged following these treatments implying translational regulation of nNOS activity. Behavioral indices indicative of exploratory behavior were also depressed in aged animals. Dietary supplementation with melatonin or acetyl L-carnitine partially reversed these changes. These findings suggest that dietary supplementation cannot merely arrest but indeed reverse some age-related increases in markers of oxidative and inflammatory events occurring with the cortex.

Acetylcarnitine↗

PubMed2002

Effects of simulated microgravity on arterial nitric oxide synthase and nitrate and nitrite content.

The aim of the present work was to investigate the alterations in nitric oxide synthase (NOS) expression and nitrate and nitrite (NOx) content of different arteries from simulated microgravity rats. Male Wistar rats were randomly assigned to either a control group or simulated microgravity group. For simulating microgravity, animals were subjected to hindlimb unweighting (HU) for 20 days. Different arterial tissues were removed for determination of NOS expression and NOx. Western blotting was used to measure endothelial NOS (eNOS) and inducible NOS (iNOS) protein content. Total concentrations of NOx, stable metabolites of nitric oxide, were determined by the chemiluminescence method. Compared with controls, isolated vessels from simulated microgravity rats showed a significant increase in both eNOS and iNOS expression in carotid arteries and thoracic aorta and a significant decrease in eNOS and iNOS expression of mesenteric arteries. The eNOS and iNOS content of cerebral arteries, as well as that of femoral arteries, showed no differences between the two groups. Concerning NOx, vessels from HU rats showed an increase in cerebral arteries, a decrease in mesenteric arteries, and no change in carotid artery, femoral artery and thoracic aorta. These data indicated that there were differential alterations in NOS expression and NOx of different arteries after hindlimb unweighting. We suggest that these changes might represent both localized adaptations to differential body fluid redistribution and other factors independent of hemodynamic shifts during simulated microgravity.

Animals↗

PubMed2002

Correction of long-term diet-induced hypertension and nitrotyrosine accumulation by diet modification.

Several recent studies have demonstrated that various forms of hypertension are associated with enhanced reactive oxygen species (ROS) activity. We have recently shown that long-term consumption of a diet similar to that ingested in westernized societies, containing high saturated fat and refined carbohydrate, induces oxidative stress and hypertension in normal rats. We hypothesized that diet modification may reverse diet-induced hypertension via (among other mechanisms) decreased ROS activity and improved nitric oxide (NO) availability. To test this hypothesis, female Fischer rats were placed on either a high-fat (primarily saturated), refined carbohydrate (sucrose) diet (HFS) or low-fat, complex-carbohydrate diet (LFCC) starting at 2 months of age. After 2 years when hypertension was well established, a group of HFS rats was converted to the LFCC diet (HFS/LFCC group) for a period of 2 months. Plasma malondialdehyde, a marker of lipid peroxidation by ROS, was elevated in the HFS group. Hypertension was present in the HFS group at 2 years as was a significant accumulation, in various tissues, of nitrotyrosine, which is the footprint of NO inactivation by ROS. Conversion from the HFS to the LFCC diet for 2 months led to normalization of blood pressure and reduced nitrotyrosine accumulation in the absence of caloric restriction. These results demonstrate that oxidative stress and hypertension induced by long-term consumption of an HFS diet are reversible with implementation of a low-fat, unrefined carbohydrate diet. The effects of the HFS diet and subsequent conversion to the LFCC diet on blood pressure appear to be, in part, mediated by changes in NO availability.

Animals↗

PubMed2002

Antioxidant therapy potentiates antihypertensive action of insulin in diabetic rats.

BACKGROUND: Poorly controlled longstanding diabetes frequently results in sustained hypertension (HTN) which plays a major role in the pathogenesis of diabetic nephropathy. In addition, hyperglycemia, per se, causes a reversible rise in blood pressure (BP) and increases production of reactive oxygen species (ROS). Increased ROS activity may raise BP by promoting inactivation of nitric oxide (NO) and/or nonenzymatic generation of vasoconstrictive prostaglandins from peroxidation of arachidonic acid. Therefore, we hypothesized that antioxidant therapy may enhance the BP-lowering effect of glycemia control with insulin replacement in diabetes. METHODS: Male Sprague-Dawley rats were rendered diabetic by streptozotocin administration and randomized to untreated, antioxidant-treated (vitamin E-fortified food, tocopherol 5000 U/kg chow and vitamin C-fortified H2O, 1000 mg/L), insulin-treated and insulin plus antioxidant-treated groups. Normal rats fed a regular diet or antioxidant-fortified diet served as controls and monitored for 4 weeks. RESULTS: The diabetic animals showed marked hyperglycemia, HTN, proteinuria, depressed tissue glutathione level and elevated plasma lipid peroxidation product, malondialdehyde (MDA) denoting increased ROS activity. Insulin therapy alone resulted in significant, but incomplete reduction in BP and plasma MDA but not proteinuria. Antioxidant therapy alone had no effect on the measured parameters in either the diabetic or control animals. However, combined insulin and antioxidant therapies normalized BP, plasma MDA and urinary protein in the diabetic animals. As expected, uncontrolled diabetes resulted in glomerular hyperfiltration which was partially reversed by insulin therapy, but was unaffected by antioxidant therapy. CONCLUSION: Uncontrolled hyperglycemia in the early phase of diabetes was associated with elevated plasma MDA, HTN and proteinuria. Insulin therapy alone resulted in significant but incomplete reduction of plasma MDA and BP. Antioxidant therapy which was ineffective when given alone, normalized plasma MDA, BP and reduced urinary protein excretion when combined with insulin treatment.

Animals↗

PubMed2002

Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency.

Chronic renal failure (CRF) is associated with oxidative stress which promotes production of reactive carbonyl compounds and lipoperoxides leading to the accumulation of advanced glycation and lipoxidation end products. Reactive oxygen species (ROS) avidly reacts with nitric oxide (NO) producing cytotoxic reactive nitrogen species capable of nitrating proteins and damaging other molecules. This study tested the hypothesis that CRF results in enhanced ROS-mediated NO inactivation and protein nitration which can be ameliorated with antioxidant therapy. Male Sprague Dawley rats were randomized to CRF (5/6 nephrectomy) and sham-operated controls and fed either a regular diet (vitamin E, 40 U/Kg food) or an antioxidant-fortified diet (vitamin E, 5000 U/Kg food) for 6 weeks. Blood pressure, plasma malondialdehyde (MDA), tissue NO synthase (NOS) isoforms, tissue nitrotyrosine (the footprint of NO interaction with ROS), and vascular tissue NO production were determined. CRF resulted in marked elevations of blood pressure, plasma MDA, and tissue nitrotyrosine abundance, but did not change plasma L-arginine level. This was coupled with depressed vascular tissue NO production and reduced immunodetectable NOS proteins in the vascular, renal, and cardiac tissues. Antioxidant therapy ameliorated the CRF-induced hypertension, improved vascular tissue NO production, lowered tissue nitrotyrosine burden, and reversed downregulations of NOS isoforms. In contrast, antioxidant therapy had no effects in the controls. CRF is associated with oxidative stress which promotes NO inactivation by ROS leading to functional NO deficiency, hypertension, and widespread accumulation of protein nitration products. Amelioration of oxidative stress by high-dose vitamin E enhances NO availability, improves hypertension, lowers protein nitration products, and increases NOS expression and vascular NO production in CRF animals.

Animals↗