Cardiac changes in apoptosis, inflammation, oxidative stress, and nitric oxide system induced by prenatal and postnatal zinc deficiency in male and female rats.

PURPOSE: Zinc restriction during fetal and postnatal development could program cardiovascular diseases in adulthood. The aim of this study was to determine the effects of zinc restriction during fetal life, lactation, and/or post-weaning growth on cardiac inflammation, apoptosis, oxidative stress, and nitric oxide system of male and female adult rats. METHODS: Wistar rats were fed a low- or a control zinc diet during pregnancy and up to weaning. Afterward, offspring were fed either a low- or a control zinc diet until 81 days of life. IL-6 and TNF-α levels, TUNEL assay, TGF-ß1 expression, thiobarbituric acid-reactive substances that determine lipoperoxidation damage, NADPH oxidase-dependent superoxide anion production, antioxidant and nitric oxide synthase activity, mRNA and protein expression of endothelial nitric oxide synthase, and serine1177 phosphorylation isoform were determined in left ventricle. RESULTS: Zinc deficiency activated apoptotic and inflammatory processes and decreased TGF-ß1 expression and nitric oxide synthase activity in cardiac tissue of both sexes. Male zinc-deficient rats showed no changes in endothelial nitric oxide synthase expression, but a lower serine1177 phosphorylation. Zinc deficiency induced an increase in antioxidant enzymes activity and no differences in lipoperoxidation products levels in males. Females were less sensitive to this deficiency exhibiting lower increase in apoptosis, lower decrease in expression of TGF-ß1, and higher antioxidant and nitric oxide enzymes activities. A zinc-adequate diet during postnatal life reversed most of these mechanisms. CONCLUSION: Prenatal and postnatal zinc deficiency induces alterations in cardiac apoptotic, inflammatory, oxidative, and nitric oxide pathways that could predispose the onset of cardiovascular diseases in adult life.

Morphological and functional effects on cardiac tissue induced by moderate zinc deficiency during prenatal and postnatal life in male and female rats.

The aim of this study was to evaluate whether moderate zinc restriction in rats throughout fetal life, lactation, and/or postweaning growth results in early changes in cardiac morphology predisposing the onset of cardiac dysfunction in adult life as well as sex-related differences in the adaptation to this nutritional injury. Female Wistar rats received low or control zinc diets from the beginning of pregnancy up to offspring weaning. After being weaned, offspring were fed either a low or control zinc diet until 81 days. Systolic blood pressure was measured. Echocardiographic and electrocardiographic examinations, morphological experiments, and apoptosis by TUNEL assay were performed in the left ventricle. In the early stages, zinc-deficient male and female offspring showed an increase in cardiomyocyte diameter, probably associated with an increase in cardiac apoptotic cells, but smaller myocyte diameters in adulthood. In adult males, this nutritional injury induced decreased contractility and dilatation of the left ventricle, not allowing the heart to compensate the higher levels of blood pressure, and hypertrophic remodeling of coronary arteries associated with increased blood pressure. Adequate zinc intake during postweaning life did not overcome blood pressure levels but reversed some of the detrimental effects of earlier zinc deficiency in cardiac morphology and function. Females were less sensitive to this deficiency, exhibiting normal levels of blood pressure and no structural or functional heart alterations in adult life. The present study demonstrates that the effects of zinc deficiency on blood pressure, cardiac morphology, and function differ between sexes, with males more predisposed to develop cardiovascular diseases in adulthood.

Hypovolemic state: age-related influence of water restriction on cardiac nitric oxide synthase in rats.

AIM OF STUDY: We have assessed the influence of water restriction stress on the nitric oxide (NO) synthase in heart and aorta tissues in young 2-month-old and middle-aged 12-month-old rats. METHODS: Animals were divided into control and 24- and 72-h water-deprived groups. We evaluated systolic blood pressure (SBP), biochemical parameters, nitrate and nitrite urinary excretion (UNOx), NADPH-diaphorase activity, and protein levels of NOS in the right atria, left ventricle, and thoracic aorta tissues. RESULTS: Water restriction during 72 h increased SBP (16%) in 2-month-old rats but decreased it after 24 and 72 h (9 and 15%, respectively) in 12-month-old rats. Atria, aorta endothelium, and smooth muscle NOS activity increased (32, 63, and 88%, respectively) only after 72 h of water restriction in 2-month-old rats. It also increased not only after 72 h but also after 24 h in atria (27 and 18%, respectively) and in ventricle (39 and 67%, respectively) in 12-month-old rats. Meanwhile, in this group's aorta smooth muscle, the enzyme activity decreased (16 and 7%, respectively). A major difference seen between ages was the changes in UNOx excretion, which decreased in the younger in 24 and 72 h (47 and 81%, respectively) and increased in the middle-aged rats (193 and 389%, respectively). Water restriction did not change cardiovascular endothelial and neuronal NOS protein levels in any group. CONCLUSION: NO pathways could contribute to the development of age-related cardiovascular adaptation to volume depletion induced by water restriction.

Zinc deficiency during growth: influence on renal function and morphology.

This study was designed to investigate the effects of moderate zinc deficiency during growth on renal morphology and function in adult life. Weaned male Wistar rats were divided into two groups and fed either a moderately zinc-deficient diet (zinc: 8 mg/kg, n=12) or a control diet (zinc: 30 mg/kg, n=12) for 60 days. We evaluated: renal parameters, NADPH-diaphorase and nitric oxide synthase activity in kidney, renal morphology and apoptotic cells in renal cortex. Zinc-deficient rats showed a decrease in glomerular filtration rate and no changes in sodium and potassium urinary excretion. Zinc deficiency decreased NADPH diaphorase activity in glomeruli and tubular segment of nephrons, and reduced activity of nitric oxide synthase in the renal medulla and cortex, showing that zinc plays an important role in preservation of the renal nitric oxide system. A reduction in nephron number, glomerular capillary area and number of glomerular nuclei in cortical and juxtamedullary areas was observed in zinc deficient kidneys. Sirius red staining and immunostaining for alpha-smooth muscle-actin and collagen III showed no signs of fibrosis in the renal cortex and medulla. An increase in the number of apoptotic cells in distal tubules and cortical collecting ducts neighboring glomeruli and, to a lesser extent, in the glomeruli was observed in zinc deficient rats. The major finding of our study is the emergence of moderate zinc deficiency during growth as a potential nutritional factor related to abnormalities in renal morphology and function that facilitates the development of cardiovascular and renal diseases in adult life.

Mild zinc deficiency in male and female rats: early postnatal alterations in renal nitric oxide system and morphology.

OBJECTIVE: Fetal and postnatal zinc deficiencies induce an increase in arterial blood pressure and impair renal function in male adult rats. We therefore hypothesized that these renal alterations are present in early stages of life and that there are sexual differences in the adaptations to this nutritional injury. The aim was to study the effects of moderate zinc deficiency during fetal life and lactation on renal morphology, oxidative stress, apoptosis, and the nitric oxide system in male and female rats at 21 d of life. METHODS: Female Wistar rats received low (8 ppm) or control (30 ppm) zinc diets from the beginning of pregnancy to weaning. Glomerulus number, morphology, oxidative stress, apoptotic cells, nitric oxide synthase activity, and protein expression were evaluated in the kidneys of offspring at 21 d. RESULTS: Zinc deficiency decreased the nephron number, induced glomerular hypertrophy, increased oxidative damage, and decreased nitric oxide synthase activity in the male and female rat kidneys. Nitric oxide synthase activity was not affected by inhibitors of the neuronal or inducible isoforms, so nitric oxide was mainly generated by the endothelial isoenzyme. Gender differences were observed in glomerular areas and antioxidant enzyme activities. CONCLUSION: Zinc deficiency during fetal life and lactation induces an early decrease in renal functional units, associated with a decrease in nitric oxide activity and an increase in oxidative stress, which would contribute to increased arterial blood pressure and renal dysfunction in adulthood. The sexual differences observed in this model may explain the dissimilar development of hypertension and renal diseases in adult life.

Zinc restriction during different periods of life: influence in renal and cardiovascular diseases.

Micronutrient undernutrition during critical periods of growth has become an important health issue in developing and developed countries, particularly among pregnant women and children having an imbalanced diet. Zinc is a widely studied microelement in infant feeding because it is a component of several enzymes involved in intermediary metabolism ranging from growth to cell differentiation and metabolism of proteins, carbohydrates, and lipids. Human and experimental studies have reported an association between zinc deficiency and the etiopathogenesis of cardiovascular and renal diseases like hypertension, atherosclerosis, congestive heart failure, coronary heart disease, and diabetes. The main links between the development of these pathologies and zinc deficiency are multiple mechanisms involving oxidative stress damage, apoptosis, and inflammation. A substantial body of evidence suggests that a poor in utero environment elicited by maternal dietary or placental insufficiency may "programme" susceptibility in the fetus to later development of cardiovascular, renal, metabolic, and endocrine diseases. Zinc deficiency in rats during intrauterine and postnatal growth can also be considered a model of fetal programming of cardiovascular and renal diseases in adult life. Dietary zinc restriction during fetal life, lactation, and/or postweaning induces an increase in arterial blood pressure and impairs renal function in adult life. This review focuses on the contributions of experimental and clinical studies to current knowledge of the physiologic role of zinc in the cardiovascular and renal systems. Moreover, this review examines the relationship between zinc deficiency during different periods of life and the development of cardiovascular and renal diseases in adult life.