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International Journal of Molecular... Nov 2022Adrenomedullin, a peptide with vasodilatory, natriuretic, and diuretic effects, may be a novel agent for treating heart failure. Heart failure is associated with an...
Adrenomedullin, a peptide with vasodilatory, natriuretic, and diuretic effects, may be a novel agent for treating heart failure. Heart failure is associated with an increased risk of atrial fibrillation (AF), but the effects of adrenomedullin on atrial arrhythmogenesis remain unclear. This study investigated whether adrenomedullin modulates the electrophysiology of the atria (AF substrate) or pulmonary vein (PV; AF trigger) arrhythmogenesis. Conventional microelectrode or whole-cell patch clamps were used to study the effects of adrenomedullin (10, 30, and 100 pg/mL) on the electrical activity, mechanical response, and ionic currents of isolated rabbit PV and sinoatrial node tissue preparations and single PV cardiomyocytes. At 30 and 100 pg/mL, adrenomedullin significantly reduced the spontaneous beating rate of the PVs from 2.0 ± 0.4 to 1.3 ± 0.5 and 1.1 ± 0.5 Hz (reductions of 32.9% ± 7.1% and 44.9 ± 8.4%), respectively, and reduced PV diastolic tension by 12.8% ± 4.1% and 14.5% ± 4.1%, respectively. By contrast, adrenomedullin did not affect sinoatrial node beating. In the presence of L-NAME (a nitric oxide synthesis inhibitor, 100 μM), adrenomedullin (30 pg/mL) did not affect the spontaneous beating rate or diastolic tension of the PVs. In the single-cell experiments, adrenomedullin (30 pg/mL) significantly reduced the L-type calcium current (I) and reverse-mode current of the sodium-calcium exchanger (NCX). Adrenomedullin reduces spontaneous PV activity and PV diastolic tension by reducing I and NCX current and thus may be useful for treating atrial tachyarrhythmia.
Topics: Animals; Rabbits; Pulmonary Veins; Adrenomedullin; Heart Atria; Atrial Fibrillation; Heart Failure
PubMed: 36430541
DOI: 10.3390/ijms232214064 -
ESC Heart Failure Aug 2023Heart failure (HF) is a frequent condition in the elderly, further complicated by associated pulmonary hypertension (PH), with impact on morbidity and mortality. Plasma...
AIMS
Heart failure (HF) is a frequent condition in the elderly, further complicated by associated pulmonary hypertension (PH), with impact on morbidity and mortality. Plasma proteins associated with cardiovascular disease, related to inflammation, neurohormonal changes, and myocyte stress, pathways recognized in the pathophysiology of HF, may provide information on disease severity and prognosis. We aimed to investigate such cardiovascular proteins and their relationship to haemodynamics before and 1 year after heart transplantation (HT), as well as their prognostic value in advanced HF with PH.
METHODS AND RESULTS
In 20 healthy controls and 67 patients with HF and PH, before and 1 year after HT, N-terminal pro-brain natriuretic peptide (NT-proBNP) and 18 cardiovascular proteins were analysed with proximity extension assay. Right heart catheterization was used to measure the haemodynamics of the HF patients pre-operatively and at 1 year follow-up after HT. Prognosis was estimated using Kaplan-Meier and Cox regression analyses. Out of 18 plasma proteins, 11 proteins including adrenomedullin peptides and precursor levels (ADM) and protein suppression of tumourigenicity 2 receptor were elevated before HT compared with healthy controls and had decreased 1 year after HT. The decrease in plasma levels 1 year after HT was towards the healthy controls' levels. The decrease in ADM levels before vs. after HT correlated with decreased mean right atrial pressure (r = 0.61; P = 0.0077), decreased NT-proBNP (r = 0.75; P = 0.00025), and decreased stroke volume index (r = -0.52; P = 0.022). High levels of pre-operative plasma ADM were associated with worse event-free survival (HT or death), as well as survival compared with low ADM levels (log-rank P value = 0.023 and 0.0225, respectively). Univariable Cox regression analysis demonstrated that ADM levels were associated with survival, hazard ratio (HR) 1.007 (95% confidence interval (CI): 1.00-1.015, P = 0.049), and the association remained after adjusting for NT-proBNP, HR 1.01 (95% CI: 1.00-1.021, P = 0.041).
CONCLUSIONS
Elevated plasma levels of ADM may be a marker of pressure/volume overload in HF patients with PH, as well as long-term prognosis after HT. In line with previous studies, our findings additionally confirm that ADM may be a marker of venous congestion in HF. Further studies are encouraged to establish a deeper understanding of the properties of ADM and its relationship with HF and PH, in order to potentially facilitate clinical management of HF and associated PH.
Topics: Humans; Aged; Adrenomedullin; Biomarkers; Prognosis; Heart Transplantation; Heart Failure; Hemodynamics
PubMed: 37246315
DOI: 10.1002/ehf2.14399 -
Biology of Reproduction Oct 2021Adrenomedullin (ADM) is an evolutionarily conserved multifunctional peptide hormone that regulates implantation, embryo spacing, and placentation in humans and rodents....
Adrenomedullin (ADM) is an evolutionarily conserved multifunctional peptide hormone that regulates implantation, embryo spacing, and placentation in humans and rodents. However, the potential roles of ADM in implantation and placentation in pigs, as a litter-bearing species, are not known. This study determined abundances of ADM in uterine luminal fluid, and the patterns of expression of ADM and its receptor components (CALCRL, RAMP2, RAMP3, and ACKR3) in uteri from cyclic and pregnant gilts, as well as conceptuses (embryonic/fetus and its extra-embryonic membranes) during the peri-implantation period of pregnancy. Total recoverable ADM was greater in the uterine fluid of pregnant compared with cyclic gilts between Days 10 and 16 post-estrus and was from uterine luminal epithelial (LE) and conceptus trophectoderm (Tr) cells. Uterine expression of CALCRL, RAMP2, and ACKR3 were affected by day (P < 0.05), pregnant status (P < 0.01) and/or day x status (P < 0.05). Within porcine conceptuses, the expression of CALCRL, RAMP2, and ACKR3 increased between Days 10 and 16 of pregnancy. Using an established porcine trophectoderm (pTr1) cell line, it was determined that 10-7 M ADM stimulated proliferation of pTr1 cells (P < 0.05) at 48 h, and increased phosphorylated mechanistic target of rapamycin (p-MTOR) and 4E binding protein 1 (p-4EBP1) by 6.1- and 4.9-fold (P < 0.0001), respectively. These novel results indicate a significant role for ADM in uterine receptivity for implantation and conceptus growth and development in pigs. They also provide a framework for future studies of ADM signaling to affect proliferation and migration of Tr cells, spacing of blastocysts, implantation, and placentation in pigs.
Topics: Adrenomedullin; Animals; Embryo, Mammalian; Female; Receptors, Adrenomedullin; Spatio-Temporal Analysis; Sus scrofa; Uterus
PubMed: 34104954
DOI: 10.1093/biolre/ioab110 -
Poultry Science Jul 2024Adrenomedullin has various physiological roles including appetite regulation. The objective of present study was to determine the effects of ICV injection of...
Adrenomedullin has various physiological roles including appetite regulation. The objective of present study was to determine the effects of ICV injection of adrenomedullin and its interaction with NPY and CCK receptors on food intake regulation. In experiment 1, chickens received ICV injection of saline and adrenomedullin (1, 2, and 3 nmol). In experiment 2, birds injected with saline, B5063 (NPY receptor antagonist, 1.25 µg), adrenomedullin (3 nmol) and co-injection of B5063+adrenomedullin. Experiments 3 to 5 were similar to experiment 2 and only SF22 (NPY receptor antagonist, 1.25 µg), SML0891 (NPY receptor antagonist, 1.25 µg) and CCK (1 nmol) were injected instead of B5063. In experiment 6, ICV injection of saline and CCK (0.125, 0.25, and 0.5 nmol) were done. In experiment 7, chickens injected with saline, CCK (0.125 nmol), adrenomedullin (3 nmol) and co-injection of CCK+adrenomedullin. After ICV injection, birds were returned to their individual cages immediately and cumulative food intake was measured at 30, 60, and 120 min after injection. Adrenomedullin (2 and 3 nmol) decreased food intake compared to control group (P < 0.05). Coinjection of B5063+adrenomedullin amplified hypophagic effect of adrenomedullin (P < 0.05). The ICV injection of the CCK (0.25 and 0.5 nmol) reduced food intake (P < 0.05). Co-injection of the CCK+adrenomedullin significantly potentiated adrenomedullin-induced hypophagia (P < 0.05). Administration of the SF22, SML0891 and CCK had no effect on the anorexigenic response evoked by adrenomedullin (P > 0.05). These results suggested that the hypophagic effect of the adrenomedullin is mediated by NPY and CCK receptors. However, our novel results should form the basis for future experiments.
Topics: Animals; Adrenomedullin; Chickens; Injections, Intraventricular; Neuropeptide Y; Eating; Female; Avian Proteins; Appetite Regulation; Male; Receptors, Cholecystokinin; Cholecystokinin
PubMed: 38772088
DOI: 10.1016/j.psj.2024.103819 -
Endocrinology Jan 2022Calcitonin gene-related peptide (CGRP) and its family members adrenomedullin (ADM) and adrenomedullin 2 (ADM2; also known as intermedin) support vascular adaptions in...
RATIONALE
Calcitonin gene-related peptide (CGRP) and its family members adrenomedullin (ADM) and adrenomedullin 2 (ADM2; also known as intermedin) support vascular adaptions in rat pregnancy.
OBJECTIVE
This study aimed to assess the relaxation response of uterine artery (UA) for CGRP, ADM, and ADM2 in nonpregnant and pregnant women and identify the involved mechanisms.
FINDINGS
(1) Segments of UA from nonpregnant women that were precontracted with U46619 (1μM) in vitro are insensitive to the hypotensive effects of CGRP, ADM, and ADM2; (2) CGRP, ADM, and ADM2 (0.1-100nM) dose dependently relax UA segments from pregnant women with efficacy for CGRP > ADM = ADM2; (3) the relaxation responses to CGRP, ADM, and ADM2 are differentially affected by the inhibitors of nitric oxide (NO) synthase (L-NAME), adenylyl cyclase (SQ22536), apamin, and charybdotoxin; (4) UA smooth muscle cells (UASMC) express mRNA for calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)1 and RAMP2 but not RAMP3; (5) receptor heterodimer comprising CRLR/RAMP1 and CRLR/RAMP2 but not CRLR/RAMP3 is present in UA; (6) soluble fms-like tyrosine kinase (sFLT-1) and TNF-α treatment decrease the expression of RAMP1 mRNA (P < 0.05) in UASMC; and (7) sFLT-1 treatment impairs the association of CRLR with all 3 peptides while TNF-α inhibits the interaction of CGRP but not ADM or ADM2 with CRLR in UASMC (P < 0.05).
CONCLUSIONS
Relaxation sensitivity of UA for CGRP, ADM, and ADM2 is increased during pregnancy via peptide-specific involvement of NO system and endothelium-derived hyperpolarizing factors; vascular disruptors such as sFLT-1 and TNFα adversely impact their receptor system in UASMC.
Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenomedullin; Apamin; Charybdotoxin; Dimerization; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Membrane Proteins; Myocytes, Smooth Muscle; Peptide Hormones; Pregnancy; RNA, Messenger; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptors, Calcitonin; Uterine Artery; Vascular Endothelial Growth Factor Receptor-1
PubMed: 34558598
DOI: 10.1210/endocr/bqab204 -
Oncotarget Oct 2017Adrenomedullin has been shown to be overexpressed in many tumors, including gastric cancer tumors; however, its mechanism of action remains unclear. In this study, we...
Adrenomedullin has been shown to be overexpressed in many tumors, including gastric cancer tumors; however, its mechanism of action remains unclear. In this study, we examined the role of adrenomedullin in the pathogenesis of gastric cancer. Using clinical specimens and immunohistochemistry, we found that the expression levels of adrenomedullin and its receptors are inordinately elevated as compared to the adjacent non-tumor gastric tissues. We used siRNA gene silencing, in BGC-823 gastric cancer cell lines, to target adrenomedullin genes, and found that increased adrenomedullin expression results in the proliferation of tumor cells, tumor invasion, and metastasis. Furthermore, we found that under hypoxic conditions, gastric cancer BGC-823 cells exhibit higher expression levels of adrenomedullin and various other related proteins. Our results indicate the involvement of adrenomedullin in microvessel proliferation and partially in the release of hypoxia in solid tumors. Knockdown of adrenomedullin expression, at the protein level, reduced the levels of phosphoprotein kinase B and B-cell lymphoma 2 but increased the levels of cleaved-caspase3 and Bcl 2 associated x protein (Bax). Therefore, we hypothesized siRNA targeting of adrenomedullin genes inhibits various serine/threonine kinases via a signaling pathway that induces cell apoptosis. SiRNA targeting of adrenomedullin genes and green fluorescent control vectors were used to transfect BGC-823 cells, and western blot analyses were used to detect changes in the rates of autophagy in related proteins using confocal laser scanning microscopy. No significant changes were detected. Therefore, the knockdown of adrenomedullin and its receptors may represent a novel treatment strategy for gastric cancer.
PubMed: 29179449
DOI: 10.18632/oncotarget.18881 -
Hypertension Research : Official... Mar 2022Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM... (Review)
Review
Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.
Topics: Adrenomedullin; Cardiovascular Diseases; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction
PubMed: 34992239
DOI: 10.1038/s41440-021-00806-y -
PloS One 2022Gestational diabetes mellitus (GDM) is associated with defective pancreatic β-cell adaptation in pregnancy, but the underlying mechanism remains obscure. Our previous...
Gestational diabetes mellitus (GDM) is associated with defective pancreatic β-cell adaptation in pregnancy, but the underlying mechanism remains obscure. Our previous studies demonstrated that GDM women display increased plasma adrenomedullin (ADM) levels, and non-obese GDM mice show decreased serum concentrations of insulin and the number of β-cells in pancreas islets. The aims of this study is to examine if ADM and its receptors are expressed in female mouse pancreas, and if so, whether insulin secretion is regulated by ADM in mouse β-cell line, NIT-1 cells and isolated mouse pancreatic islets. Present study shows that ADM and its receptor components CRLR, RAMPs are present in mouse pancreatic islets and co-localized with insulin. The expressions of ADM, CRLR and RAMP2 in islets from pregnant mice are reduced compared to that of non-pregnant mice. NIT-1-β cells express ADM and its receptor mRNA, and glucose dose-dependently stimulates expressions. Furthermore, ADM inhibits NIT-1-β cell growth, and this inhibition is reversed by ADM antagonist, ADM22-52. The glucose-induced insulin secretion was suppressed by ADM in NIT-1-β cells and isolated pancreatic islets from pregnant mice. These inhibitory effects are accompanied by upregulation of endoplasmic reticulum (ER) stress biomarker genes in NIT-1-β cells. This study unveils that reduced ADM and its receptors may play a role in β-cell adaptation during pregnancy, while increased plasma ADM in GDM may contribute to the β-cells dysfunction, and blockade of ADM may reverse β-cell insulin production.
Topics: Adrenomedullin; Animals; Diabetes, Gestational; Female; Glucose; Humans; Insulin; Insulin, Regular, Human; Insulin-Secreting Cells; Mice; Pregnancy; Receptors, Adrenomedullin
PubMed: 35324977
DOI: 10.1371/journal.pone.0265890 -
European Journal of Heart Failure Feb 2019Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses... (Review)
Review
Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin-angiotensin-aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio-ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio-ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non-neutralizing ADM-binding antibody with a half-life of 15 days. Adrecizumab binds at the N-terminal epitope of ADM, leaving the C-terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM-binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.
Topics: Adrenomedullin; Animals; Biomarkers; Cardiotonic Agents; Heart Failure; Humans; Molecular Targeted Therapy; Stroke Volume
PubMed: 30592365
DOI: 10.1002/ejhf.1366 -
International Journal of Molecular... Dec 2023Sepsis causes immune dysregulation and endotheliitis, with an increase in mid-regional pro-adrenomedullin (MR-proADM). The aim of the study is to determine an MR-proADM...
Sepsis causes immune dysregulation and endotheliitis, with an increase in mid-regional pro-adrenomedullin (MR-proADM). The aim of the study is to determine an MR-proADM value that, in addition to clinical diagnosis, can identify patients with localized infection or those with sepsis/septic shock, with specific organ damage or with the need for intensive care unit (ICU) transfer and prognosis. The secondary aim is to correlate the MR-proADM value with the length of stay (LOS). In total, 301 subjects with sepsis (124/301 with septic shock) and 126 with localized infection were retrospectively included. In sepsis, MR-proADM ≥ 3.39 ng/mL identified acute kidney injury (AKI); ≥2.99 ng/mL acute respiratory distress syndrome (ARDS); ≥2.28 ng/mL acute heart failure (AHF); ≥2.55 ng/mL Glascow Coma Scale (GCS) < 15; ≥3.38 multi-organ involvement; ≥3.33 need for ICU transfer; ≥2.0 Sequential Organ Failure Assessment (SOFA) score ≥ 2; and ≥3.15 ng/mL non-survivors. The multivariate analysis showed that MR-proADM ≥ 2 ng/mL correlates with AKI, anemia and SOFA score ≥ 2, and MR-proADM ≥ 3 ng/mL correlates with AKI, GCS < 15 and SOFA score ≥ 2. A correlation between mortality and AKI, GCS < 15, ICU transfer and cathecolamine administration was found. In localized infection, MR-proADM at admission ≥ 1.44 ng/mL identified patients with AKI; ≥1.0 ng/mL with AHF; and ≥1.44 ng/mL with anemia and SOFA score ≥ 2. In the multivariate analysis, MR-proADM ≥ 1.44 ng/mL correlated with AKI, anemia, SOFA score ≥ 2 and AHF. MR-proADM is a marker of oxidative stress due to an infection, reflecting severity proportionally to organ damage.
Topics: Humans; Shock, Septic; Retrospective Studies; Adrenomedullin; Biomarkers; Sepsis; Heart Failure; Acute Kidney Injury; Anemia
PubMed: 38139258
DOI: 10.3390/ijms242417429