Variations of Human Adrenomedullin Gene and Its Relation to Cardiovascular Diseases

Ishimitsu, Toshihiko; Tsukada, Kohju; Minami, Junichi; Ono, Hitoshi; Matsuoka, Hiroaki

doi:10.1291/hypres.26.s129

Cited by 18 publications

(13 citation statements)

References 50 publications

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“…It is likely that IL-8 induces an AP-response in DAOY and SWB40 that is consistent with inhibition of NF-B subunit transcription and subsequent activation (12)(13)(14). Methionine stress also results in up-regulation of the already highly expressed NF-IL6 and subsequent increase of the adrenomedullin signal (15) in all of the methionine-dependent cell lines. High expression of NF-IL6 and adrenomedullin is in agreement with the active involvement of phospholipase C and protein kinase C in SWB77, regardless of culture conditions.…”

Section: Mechanisms Of Methionine-stress Toxicitymentioning

confidence: 61%

Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress

Kokkinakis

Liu

Chada³

et al. 2004

Cancer Research

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Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45␣ and ␥ in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of MDA7 and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress downregulated the highly active phosphatidylinositol 3-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor B under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.

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Section: Mechanisms Of Methionine-stress Toxicitymentioning

confidence: 61%

Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress

Kokkinakis

Liu

Chada³

et al. 2004

Cancer Research

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“…Both preeclampsia and placenta accreta are associated with significant maternal mortality and fetal complications, yet the etiological or genetic factors leading to these conditions remain unclear. Genetic polymorphisms in the human AM gene have been associated with alterations in basal blood pressure and diabetic nephropathy (66,67). Thus, our current studies with heterozygote mice that have a genetic reduction in AM expression not only provide insights into the role AM has in the processes of implantation and fetal growth but further raise the intriguing possibility that modest alterations in AM gene expression in the human population may contribute significantly to overall reproductive health.…”

Section: Figurementioning

confidence: 82%

Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice

Li¹,

Yee²,

Magnuson³

et al. 2006

J. Clin. Invest.

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Adrenomedullin (AM) is a multifunctional peptide vasodilator that is essential for life. Plasma AM expression dramatically increases during pregnancy, and alterations in its levels are associated with complications of pregnancy including fetal growth restriction (FGR) and preeclampsia. Using AM +/-female mice with genetically reduced AM expression, we demonstrate that fetal growth and placental development are seriously compromised by this modest decrease in expression. AM +/-female mice had reduced fertility characterized by FGR. The incidence of FGR was also influenced by the genotype of the embryo, since AM -/-embryos were more often affected than either AM +/-or AM +/+ embryos. We demonstrate that fetal trophoblast cells and the maternal uterine wall have coordinated and localized increases in AM gene expression at the time of implantation. Placentas from growth-restricted embryos showed defects in trophoblast cell invasion, similar to defects that underlie human preeclampsia and placenta accreta. Our data provide a genetic in vivo model to implicate both maternal and, to a lesser extent, embryonic levels of AM in the processes of implantation, placentation, and subsequent fetal growth. This study provides the first genetic evidence to our knowledge to suggest that a modest reduction in human AM expression during pregnancy may have an unfavorable impact on reproduction.

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“…When combined with mice that are heterozygous for a targeted deletion of the AM gene, these mice provide a genetically controlled series of animals with variations in AM gene expression that range from Ϸ50-140% wild-type levels. This ''gene titration'' is therefore useful for modeling any modest variations in AM gene expression that may occur in the human population because of genetic polymorphisms of the AM gene (29,30). As opposed to conventional transgenic approaches where a tissue-specific promoter drives the expression of a randomly inserted transgene, the gene-titration model offers the advantage of retaining the normal location of the duplicated gene, driven by the endogenous promoter.…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males

Caron¹,

Hagaman

Nishikimi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Adrenomedullin (AM) is a potent vasodilator peptide in plasma at picomolar levels. Polymorphisms in the human AM gene have been associated with genetic predisposition to diabetic nephropathy and proteinuria with essential hypertension, and numerous studies have demonstrated that endogenous AM plays a role in protecting the heart and kidneys from fibrosis resulting from cardiovascular disease. Elevated plasma levels of AM are associated with pregnancy and sepsis and with cardiovascular stress and hypertension. However, there are no reports of the effects of genetic differences in the expression of the endogenous AM gene and of gender on blood pressure in these circumstances or on the pathological changes accompanying hypertension. To address these questions, we have generated mice having genetically controlled levels of AM mRNA ranging from Ϸ50% to Ϸ140% of wild-type levels. These modest changes in AM gene expression have no effect on basal blood pressure. Although pregnancy and sepsis increase plasma AM levels, genetically reducing AM production does not affect the transient hypotension that occurs during normal pregnancy or that is induced by treatment with lipopolysaccharide. Nor does the reduction of AM affect chronic hypertension caused by a renin transgene. However, 50% normal expression of AM enhances cardiac hypertrophy and renal damage in male, but not female, mice with a renin transgene. These observations suggest that the effect of gender on the role of AM in counteracting cardiovascular damage in humans merits careful evaluation. cardiovascular ͉ pregnancy ͉ cardiac hypertrophy ͉ renal fibrosis ͉ gene targeting A drenomedullin (AM) is a 52-aa peptide vasodilator which circulates in the plasma as a protein-bound hormone and can influence many biological processes (1). The gene coding for AM is widely expressed throughout the body, most highly in endothelial cells and vascular smooth muscle cells (2, 3). Consequently, highly vascularized tissues, such as the placenta, lung, heart, and kidney cause elevated plasma AM levels when their secretion of AM peptide is stimulated by conditions such as pregnancy, sepsis, and cardiovascular disease or by inflammatory cytokines or hypoxia.AM is most widely known for its vasodilatory properties (4). Bolus injection or infusion of AM in humans (5-10) and in several animal species (11-17) causes prolonged, dosedependent vasorelaxation and hypotension. Yet the dose, route, and duration of exogenous administration required to elicit a systemic effect on blood pressure (BP) varies widely among published studies (8-10). Moreover, it is possible that bolus infusions of the unbound peptide may not accurately replicate the functions of the endogenous protein-bound peptide. Consequently, it is important to determine whether modest changes in expression of the endogenous AM gene affect the maintenance of BP during health and disease.Endogenous AM plays a role in protecting the heart and kidneys from damage during cardiovascular stresses such as hypertension and its associated ...

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Variations of Human Adrenomedullin Gene and Its Relation to Cardiovascular Diseases

Cited by 18 publications

References 50 publications

Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress

Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress

Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice

Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males

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