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European Journal of Heart Failure Aug 2023Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment.
METHODS AND RESULTS
Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status.
CONCLUSIONS
MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure.
CLINICAL TRIAL REGISTRATION
PROVE-HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588.
Topics: Humans; Heart Failure; Adrenomedullin; Neprilysin; Microcirculation; Tetrazoles; Angiotensin Receptor Antagonists; Stroke Volume; Valsartan; Aminobutyrates; Biphenyl Compounds; Drug Combinations
PubMed: 37401523
DOI: 10.1002/ejhf.2957 -
Indian Journal of Critical Care... Dec 2020Adrenomedullin (ADM) is a 52 amino acid containing free circulating vasoactive peptide hormone found to be active in various pathophysiological states including sepsis....
Adrenomedullin (ADM) is a 52 amino acid containing free circulating vasoactive peptide hormone found to be active in various pathophysiological states including sepsis. High ADM levels at admission have been correlated with vasopressor requirements, organ dysfunction, and mortality in sepsis patients. ADM stimulation results in vasodilation and loss of vascular resistance in humans resulting in hypotension with the potential for negative impact in septic shock. However, human and animal experiments have shown that ADM decreases hyperpermeability and capillary leak, thus having an endothelial barrier stabilizing effect during septic shock. Adrenomedullin thus appears to be a double-edged weapon. This editorial critically reviews the article by Daga et al. who evaluated serum ADM as a prognostic marker to review the gender-related difference in mortality pattern, and also the correlation of ADM level to APACHE II and SOFA scores. The role of adrenomedullin in sepsis and the potential developments in the future have been discussed concisely. Ajith Kumar AK. Adrenomedullin in Sepsis: Finally, a Friend or an Enemy? Indian J Crit Care Med 2020;24(12):1151-1153.
PubMed: 33446960
DOI: 10.5005/jp-journals-10071-23669 -
Biomedicines Feb 2022The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines,... (Review)
Review
The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study.
PubMed: 35327335
DOI: 10.3390/biomedicines10030533 -
Circulation Research Apr 2023Numerous clinical studies have revealed the utility of circulating AM (adrenomedullin) or MR-proAM (mid-regional proAM 45-92) as an effective prognostic and diagnostic... (Review)
Review
Numerous clinical studies have revealed the utility of circulating AM (adrenomedullin) or MR-proAM (mid-regional proAM 45-92) as an effective prognostic and diagnostic biomarker for a variety of cardiovascular-related pathophysiologies. Thus, there is strong supporting evidence encouraging the exploration of the AM-CLR (calcitonin receptor-like receptor) signaling pathway as a therapeutic target. This is further bolstered because several drugs targeting the shared CGRP (calcitonin gene-related peptide)-CLR pathway are already Food and Drug Administration-approved and on the market for the treatment of migraine. In this review, we summarize the AM-CLR signaling pathway and its modulatory mechanisms and provide an overview of the current understanding of the physiological and pathological roles of AM-CLR signaling and the yet untapped potentials of AM as a biomarker or therapeutic target in cardiac and vascular diseases and provide an outlook on the recently emerged strategies that may provide further boost to the possible clinical applications of AM signaling.
Topics: Adrenomedullin; Calcitonin Gene-Related Peptide; Cardiovascular System; Receptor Activity-Modifying Protein 2; Signal Transduction; Humans
PubMed: 37104556
DOI: 10.1161/CIRCRESAHA.123.321673 -
The Journal of Experimental Medicine Jan 2023Within the tumor microenvironment, tumor cells and endothelial cells regulate each other. While tumor cells induce angiogenic responses in endothelial cells, endothelial...
Within the tumor microenvironment, tumor cells and endothelial cells regulate each other. While tumor cells induce angiogenic responses in endothelial cells, endothelial cells release angiocrine factors, which act on tumor cells and other stromal cells. We report that tumor cell-derived adrenomedullin has a pro-angiogenic as well as a direct tumor-promoting effect, and that endothelium-derived CC chemokine ligand 2 (CCL2) suppresses adrenomedullin-induced tumor cell proliferation. Loss of the endothelial adrenomedullin receptor CALCRL or of the G-protein Gs reduced endothelial proliferation. Surprisingly, tumor cell proliferation was also reduced after endothelial deletion of CALCRL or Gs. We identified CCL2 as a critical angiocrine factor whose formation is inhibited by adrenomedullin. Furthermore, CCL2 inhibited adrenomedullin formation in tumor cells through its receptor CCR2. Consistently, loss of endothelial CCL2 or tumor cell CCR2 normalized the reduced tumor growth seen in mice lacking endothelial CALCRL or Gs. Our findings show tumor-promoting roles of adrenomedullin and identify CCL2 as an angiocrine factor controlling adrenomedullin formation by tumor cells.
Topics: Animals; Mice; Adrenomedullin; Cell Proliferation; Chemokine CCL2; Chemokines; Endothelial Cells; Ligands; Neoplasms; Receptors, CCR2; Tumor Microenvironment
PubMed: 36374225
DOI: 10.1084/jem.20211628 -
EBioMedicine Feb 2024Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.
METHODS
We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis.
FINDINGS
We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk.
INTERPRETATION
Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.
FUNDING
Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
Topics: Adult; Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Risk; Neoplasms; Inflammation; Polymorphism, Single Nucleotide
PubMed: 38301482
DOI: 10.1016/j.ebiom.2024.104991 -
Neural Regeneration Research Jul 2020Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the... (Review)
Review
Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the role of adrenomedullin in neuropathological disorders, including pathological pain, brain injury and nerve regeneration, and their treatment. As a newly characterized pronociceptive mediator, adrenomedullin has been shown to act as an upstream factor in the transmission of noxious information for various types of pathological pain including acute and chronic inflammatory pain, cancer pain, neuropathic pain induced by spinal nerve injury and diabetic neuropathy. Initiation of glia-neuron signaling networks in the peripheral and central nervous system by adrenomedullin is involved in the formation and maintenance of morphine tolerance. Adrenomedullin has been shown to exert a facilitated or neuroprotective effect against brain injury including hemorrhagic or ischemic stroke and traumatic brain injury. Additionally, adrenomedullin can serve as a regulator to promote nerve regeneration in pathological conditions. Therefore, adrenomedullin is an important participant in nervous system diseases.
PubMed: 31960799
DOI: 10.4103/1673-5374.272567 -
Nature Communications Nov 2022DNA:DNA:RNA triplexes that are formed through Hoogsteen base-pairing of the RNA in the major groove of the DNA duplex have been observed in vitro, but the extent to...
DNA:DNA:RNA triplexes that are formed through Hoogsteen base-pairing of the RNA in the major groove of the DNA duplex have been observed in vitro, but the extent to which these interactions occur in cells and how they impact cellular functions remains elusive. Using a combination of bioinformatic techniques, RNA/DNA pulldown and biophysical studies, we set out to identify functionally important DNA:DNA:RNA triplex-forming long non-coding RNAs (lncRNA) in human endothelial cells. The lncRNA HIF1α-AS1 was retrieved as a top hit. Endogenous HIF1α-AS1 reduces the expression of numerous genes, including EPH Receptor A2 and Adrenomedullin through DNA:DNA:RNA triplex formation by acting as an adapter for the repressive human silencing hub complex (HUSH). Moreover, the oxygen-sensitive HIF1α-AS1 is down-regulated in pulmonary hypertension and loss-of-function approaches not only result in gene de-repression but also enhance angiogenic capacity. As exemplified here with HIF1α-AS1, DNA:DNA:RNA triplex formation is a functionally important mechanism of trans-acting gene expression control.
Topics: Humans; RNA, Long Noncoding; Endothelial Cells; DNA; Base Pairing; Oligonucleotides; Gene Expression Regulation, Neoplastic
PubMed: 36323673
DOI: 10.1038/s41467-022-34252-2 -
Cells Nov 2023Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management... (Review)
Review
Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.
Topics: Humans; Calcitonin Gene-Related Peptide; Gastrointestinal Hormones; Migraine Disorders; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Secretin; Vasoactive Intestinal Peptide
PubMed: 37998384
DOI: 10.3390/cells12222649 -
Children (Basel, Switzerland) Aug 2022Adrenomedullin has several properties. It acts as a potent vasodilator, has natriuretic effects, and reduces endothelial permeability. It also plays a role in initiating... (Review)
Review
Adrenomedullin has several properties. It acts as a potent vasodilator, has natriuretic effects, and reduces endothelial permeability. It also plays a role in initiating the early hyperdynamic phase of sepsis. Since its discovery, many articles have been published studying the uses and benefits of this biomarker. The aim of this review is to determine the usefulness of adrenomedullin in pediatric patients. Relevant studies covering adrenomedullin in pediatrics (<18 years) and published up until August 2021 were identified through a search of MEDLINE, PubMed, Embase, Web of Science, Scopus, and Cochrane. Seventy studies were included in the present review, most of them with a low level of evidence (IV to VI). Research on adrenomedullin has primarily been related to infection and the cardiovascular field. The performance of adrenomedullin to quantify infection in children seems satisfactory, especially in sepsis. In congenital heart disease, this biomarker seems to be a useful indicator before, during, and after cardiopulmonary bypass. Adrenomedullin seems to be useful in the pediatric population for a large variety of pathologies, especially regarding infection and cardiovascular conditions. However, it should be used in combination with other biomarkers and clinical or analytical variables, rather than as a single tool.
PubMed: 36010070
DOI: 10.3390/children9081181