Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II

Lj, Pearson; Rait, C; Nicholls, M. Gary; Yandle, Tim G.; Jg, Evans

doi:10.1677/joe.1.06815

Cited by 22 publications

(17 citation statements)

References 46 publications

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“…In marked contrast, in female mice, the degree of cardiovascular damage induced by the RenTgMK transgene is unaffected by the reduction in AM levels. Recently, Pearson et al (38) found that estrogen and testosterone have different effects on the amount of AM secreted from angiotensin II-stimulated human endothelial cells, suggesting that an interplay between sex steroids and angiotensin II may account for the gender differences observed in our study. These findings clearly demonstrate that the tissue damage caused by hypertension is enhanced in male, but not in female, mice when AM levels are decreased.…”

Section: Discussionmentioning

confidence: 49%

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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Section: Discussionmentioning

confidence: 49%

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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“…Using the cell immunoblot assay that is a sensitive and specific method to detect peptide secretion from individual cells [23,24], we observed, for the first time, time and dose dependent IMD peptide release from human endothelial cells. As for IMD mRNA, 0.75M H 2 O 2 elicited significant IMD peptide responses in HAEC.…”

Section: Discussionmentioning

confidence: 95%

“…RNA was extracted using the RNeasy Mini Kit (Qiagen, Clifton Hill, Vic, Australia) as previously described [23]. Bioinformatically validated primers (Qiagen) including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Qiagen Cat no QT 00079247), ADM (QT00223846) and IMD (QT00222173) were used for human samples.…”

Section: Rt-pcrmentioning

confidence: 99%

Intermedin (Adrenomedullin-2): a Potential Protective Role in Human Aortic Endothelial Cells

Pearson

Yandle²,

Nicholls³

et al. 2009

Cell Physiol Biochem

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Background/Aims: Intermedin (IMD) is a novel peptide with significant vasodilator and cardiac protective actions similar to the related peptide adrenomedullin (ADM). Unlike those of ADM the actions and expression of IMD in endothelial cells are poorly characterised. ADM expression can be increased during cardiovascular disease/stress in vitro and in vivo where it may have a role in several cardiovascular protective actions. To characterise IMD mRNA expression cultured human aortic endothelial cells (HAEC) were stressed by removing serum and bicarbonate, and the addition of hydrogen peroxide. The responses were compared to those of ADM mRNA. We also compared the effects of ADM and IMD on caspase activity and cell viability, and investigated if IMD actions could be altered by a CGRP receptor antagonist. Methods/Results: Using the cell immunoblot assay, immunoreactive IMD was shown to be secreted by HAEC. IMD mRNA expression was also detected in HAEC grown in endothelial growth media (but at markedly lower levels than that of ADM). Absence of bicarbonate, a redox-mediated regulator of endothelial response to various stresses, increased IMD mRNA and ADM mRNA expression. However IMD mRNA, but not ADM mRNA, was markedly increased over time in HAEC in conditions of cell stress including incubation with serum-free Dulbecco’s modified Eagle’s medium (DMEM) and in response to hydrogen peroxide (H₂O₂). These vigorous responses in IMD mRNA expression were further enhanced by incubation in 5% serum in DMEM without bicarbonate, but in a selective manner since ADM expression was suppressed by serum. We also observed that IMD mRNA was markedly increased and ADM mRNA suppressed in HAEC following a period of suspension and replating. Finally, we observed that IMD, like ADM, increased cell viability in HAEC in DMEM without serum but only IMD reduced caspase activity, perhaps via and a yet to be defined receptor system. Conclusion: HAECs express IMD mRNA and secrete IMD peptide. IMD mRNA expression is markedly dependent on metabolic conditions and is selectively regulated in a contrary fashion to ADM mRNA. IMD mRNA expression in endothelial cells is markedly sensitive to oxidative stress, and IMD peptide itself has antiapoptotic activity in human endothelial cells. Our data suggest that IMD has a different role to ADM and may perform a protective function in humans.

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“…Previously we have demonstrated that AMBP-1, a specific binding protein for AM that potentiates its effects, is able to enhance AM-induced relaxation of aortic rings taken from normal animals (29). Additionally, a decreased level of AMBP-1 in humans is associated with higher susceptibility to recurrent infections (21, 44). We have also shown that the decreased level of AMBP-1 in animal studies leads to reduced vascular responsiveness in AM, thus contributing to the vascular collapse after hemorrhagic shock and severe sepsis (25, 26).…”

Section: Discussionmentioning

confidence: 99%

“…It is widely distributed in the endocrine and neuroendocrine system (21), suggesting that AM plays an important role in the control of systemic and local circulation, as well as cardiovascular and fluid regulation, regulation of growth and differentiation, and secretions of other hormones (22). A specific binding protein to AM, adrenomedullin binding protein-1 (AMBP-1) was identified in human plasma and the purified protein was reported to be identical to human complement factor H (23).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Renal Ischemia and Reperfusion Injury by Human Adrenomedullin and its Binding Protein

Shah

Rajan

Jacob

et al. 2010

Journal of Surgical Research

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Background Acute renal failure secondary to ischemia and reperfusion (I/R) injury poses a significant burden on both surgeons and patients. It carries a high morbidity and mortality rate and no specific treatment currently exists. Major causes of renal I/R injury include trauma, sepsis, hypoperfusion, and various surgical procedures. We have demonstrated that adrenomedullin (AM), a novel vasoactive peptide, combined with AM binding protein-1 (AMBP-1), which augments the activity of AM, is beneficial in various disease conditions. However, it remains unknown whether human AM/AMBP-1 provides any beneficial effects in renal I/R injury. The objective of our study therefore was to determine whether administration of human AM/AMBP-1 can prevent and/or minimize damage in a rat model of renal I/R injury. Methods Male adult rats were subjected to renal I/R injury by bilateral renal pedicle clamping with microvascular clips for 60 min followed by reperfusion. Human AM (12 µg/kg BW) and human AMBP-1 (40 µg/kg BW) or vehicle (52 µg/kg BW human albumin) were given intravenously over 30 min immediately following the clip removal (i.e., reperfusion). Rats were allowed to recover for 24 h post treatment, and blood and renal tissue samples were collected. Plasma levels of AM were measured using a radioimmunoassay specific for rat AM. Plasma AMBP-1 was measured by Western analysis. Renal water content and serum levels of systemic markers of tissue injury were measured. Serum and renal TNF-α levels were also assessed. Results At 24 h after renal I/R injury, plasma levels of AM were significantly increased while plasma AMBP-1 was markedly decreased. Renal water content and systemic markers of tissue injury (e.g., creatinine, BUN, AST and ALT) were significantly increased following renal I/R injury. Serum and renal TNF-α levels were also increased post injury. Administration of human AM/AMBP-1 decreased renal water content, and plasma levels of creatinine, BUN, AST and ALT. Serum and renal TNF-α levels were also significantly decreased after AM/AMBP-1 treatment. Conclusion Treatment with human AM/AMBP-1 in renal I/R injury significantly attenuated organ injury and the inflammatory response. Thus, human AM combined with human AMBP-1 may be developed as a novel treatment for patients with acute renal I/R injury.

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Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II

Cited by 22 publications

References 46 publications

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

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

Intermedin (Adrenomedullin-2): a Potential Protective Role in Human Aortic Endothelial Cells

Attenuation of Renal Ischemia and Reperfusion Injury by Human Adrenomedullin and its Binding Protein

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