Cardioprotective Effect of Adrenomedullin in Heart Failure

Nishikimi, Toshio; Yoshihara, Fumiki; Mori, Yoshihide; Kangawa, Kenji; Matsuoka, Hiroaki

doi:10.1291/hypres.26.s121

Cited by 53 publications

(45 citation statements)

References 48 publications

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“…3,[27][28][29] The mechanism by which AM exerts its effects on cardiomyocytes is not fully understood. A previous report showed that AM signaling depends on the combination of CRLR (calcitonin receptor-like receptor) and RAMP2 (receptor activity- modifying proteins), resulting in activation of the AM receptor.…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

2004

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Abstract-Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3␤) but reduced GSK-3␤ and caspase-3 activities in the heart. The effects of AM on GSK-3␤ and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3␤ but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

2004

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“…Endogenous AM plays a role in protecting the heart and kidneys from damage during cardiovascular stresses such as hypertension and its associated cardiac hypertrophy, myocardial infarction, heart failure, and atherosclerosis (18,19). Thus, comparisons between male mice with genetically reduced levels of AM (AM ϩ/Ϫ ) and wild-type mice (AM ϩ/ϩ ) have demonstrated that the reduced level of endogenous AM increases the damage to heart and renal tissue caused by aortic banding (20), angiotensin II infusion (20,21), bilateral renal artery clamping (22), and atherosclerosis (23).…”

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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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“…Adrenomedullin is now recognized as a key peptide in many tissues in many species that serves as a coordinating tissue survival factor in many species during decompensating stress [6,7,42]. Examples of activity include its capacity to ameliorate regional ischemic events and blood shunting during sepsis by maintaining local tissue oxygen perfusion and blood flow [43], reducing tissue necrosis and apoptosis through AM/AM-BP complex-augmented production of anti-apoptotic BCL-2 cascade factors and concomitantly decreased pro-apoptotic Bax gene expression [44], effects on pancreatic hormone secretion and localized tissue metabolic responses to pancreatic hormones [13,29,30], interactions with the LPS-TNF-␣-nitric oxide cascade [12,13,38], and its effects to neutralize growth and pathogenic activities of both Gram-negative and Gram-positive [8][9][10] bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the activity of AM-BP as complement factor-H (responsible cofactor for the factor I-dependant cleaving of complement C3B) is increased when AM is bound [17] suggesting that aspects of the innate complement cascade within the mammary gland [49] are also modulated by AM. Furthermore, increased beneficial clinical outcome (decreased morbidity and mortality) recently has been attributed to the use of an AM/AM-BP complex as an intervention strategy to limit the complicating effects of sepsis and hypovolumic shock on progression into multiple organ failure [19,[42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin (AM) and adrenomedullin binding protein (AM-BP) in the bovine mammary gland and milk: Effects of stage of lactation and experimental intramammary E. coli infection

Elsasser

Capuco

Caperna

et al. 2007

Domestic Animal Endocrinology

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(AM) and adrenomedullin binding protein (AM-BP) in the bovine mammary gland and milk: Effects of stage of lactation and experimental intramammary E. coli infection" (2007 AbstractAdrenomedullin (AM) has been characterized as an endogenous tissue survival factor and modulator of many inflammatory processes. Because of the increased susceptibility of the mammary gland to infection during the time surrounding parturition in the cow, we investigated how milk and tissue content of AM and its binding protein (AM-BP) might be affected by the stage of lactation and the udder health status. Milk and mammary biopsy samples were obtained from Holstein cows 21 days prior to and at various times after calving to represent the dry period and early and midstages of lactation. Additional cows received an intramammary challenge with Escherichia coli for immunohistochemical characterization of AM and AM-BP. Milk AM concentrations were relatively constant across the stages of lactation while AM-BP increased two-fold (P < 0.04) between early and ଝ This article is a U.S. Government work and, as such, is in the public domain in the U.S.A. Mention of a brand name or product does not constitute an endorsement of that product by the U.S. Government where other suitably related products are adequately functional in a similar application. This article is a U.S. government work, and is not subject to copyright in the United States. T.H. Elsasser et al. / Domestic Animal Endocrinology 32 (2007) 138-154139 mid-lactation. Milk AM (P < 0.04) and AM-BP (P < 0.03) increased as somatic cell counts (SCCs) increased within a given stage of lactation. Tissue content of both (AM and AM-BP) were significantly affected by stage of lactation, lowest in the dry period and progressively increasing to peak at mid-lactation as well as increasing in association with higher levels of SCCs. Following E. coli challenge, AM increased in epithelial cells surrounding mammary alveoli presenting high levels of SCCs. The data suggest that AM and AM-BP are cooperatively regulated in the mammary gland during lactation; changes in localized tissue AM and AM-BP content reflect a dynamic regulation of these tissue factors in the bovine mammary gland consistent with their protective effects within inflamed tissue. Published by Elsevier Inc.

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Cardioprotective Effect of Adrenomedullin in Heart Failure

Cited by 53 publications

References 48 publications

Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

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

Adrenomedullin (AM) and adrenomedullin binding protein (AM-BP) in the bovine mammary gland and milk: Effects of stage of lactation and experimental intramammary E. coli infection

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