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Clinical Medicine & Research Nov 2005Fibrosis (progressive scarring) is a leading cause of organ failure worldwide and causes loss of organ function when normal tissue is replaced with excess connective... (Review)
Review
Fibrosis (progressive scarring) is a leading cause of organ failure worldwide and causes loss of organ function when normal tissue is replaced with excess connective tissue. Several organs are prone to this process regardless of etiology. The pleiotropic hormone, relaxin, is emerging as a novel antifibrotic therapy. Relaxin has been shown to limit collagen production and reorganization, while stimulating increased collagen degradation. It not only prevents fibrogenesis, but also reduces established scarring. This review summarizes (1) the levels at which relaxin inhibits collagen production and existing collagen overexpression in induced models of fibrosis, and (2) the collagen-related phenotypes of relaxin- and LGR7-deficient mice. Recent studies on relaxin-deficient mice have established relaxin as an important, naturally occurring regulator of collagen turnover and provide new insights into the therapeutic potential of relaxin.
Topics: Animals; Collagen; Disease Models, Animal; Disease Progression; Fibrosis; Gene Expression Regulation; Humans; Mice; Mice, Knockout; Models, Biological; Phenotype; Receptors, G-Protein-Coupled; Receptors, Peptide; Relaxin
PubMed: 16303890
DOI: 10.3121/cmr.3.4.241 -
Annals of the New York Academy of... Apr 2009Relaxin has beneficial effects upon the endometrium which are responsible for establishment of pregnancy. We have demonstrated that relaxin stimulates endometrial... (Review)
Review
Relaxin has beneficial effects upon the endometrium which are responsible for establishment of pregnancy. We have demonstrated that relaxin stimulates endometrial decidualization, the structural and biochemical changes in endometrial parenchymal cells, and the accompanying angiogenesis, modulation of matrix metalloproteinase activity, and increased concentrations in local immune cells which are required for implantation. Our recent data also demonstrate that either too much or too little relaxin can be detrimental. Elevated circulating maternal relaxin concentrations (hyperrelaxinemia) are associated with premature birth. This is likely due to the effects of relaxin at the level of the cervix, via upsetting the balance in the maintenance of cervical connective tissue architecture. In addition, the absence of circulating relaxin during pregnancy in women may have negative consequences upon glucose metabolism.
Topics: Cervix Uteri; Endometrium; Female; Glucose; Humans; Pregnancy; Premature Birth; Relaxin
PubMed: 19416173
DOI: 10.1111/j.1749-6632.2008.03800.x -
International Journal of Molecular... Jun 2022Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia-reperfusion...
Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia-reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups ( = 10/group), were pretreated with either saline, 5 μg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI.
Topics: Animals; Epoetin Alfa; Erythropoietin; Female; Humans; Rats; Rats, Wistar; Recombinant Proteins; Relaxin; Reperfusion Injury; Superoxide Dismutase; Uterus
PubMed: 35806125
DOI: 10.3390/ijms23137120 -
PloS One 2018'Healthy' aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold...
BACKGROUND
'Healthy' aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in recent clinical trials, Relaxin-therapy for 2-days could reduce mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin's short life-span (hours) but long-lasting protective actions led us to test the hypothesis that relaxin acts at a genomic level to reverse maladaptive remodeling in aging and HF.
METHODS AND RESULTS
Young (9-month) and aged (24-month), male and female F-344/Brown Norway rats were treated with relaxin (0.4 mg/kg/day) for 2-weeks delivered by subcutaneous osmotic mini-pumps or with sodium acetate (controls). The genomic effects of aging and relaxin were evaluated by extracting RNA from the left ventricles and analyzing genomic changes by RNA-sequencing, Ingenuity Pathway Analysis, MetaCore and tissue immunohistochemistry. We found that aging promotes a native inflammatory response with distinct sex-differences and relaxin suppresses transcription of multiple genes and signaling pathways associated with inflammation and HF in both genders. In addition, aging significantly increased: macrophage infiltration and atrial natriuretic peptide levels in female ventricles, and activation of the complement cascade, whereas relaxin reversed these age-related effects.
CONCLUSION
These data support the hypothesis that relaxin alters gene transcription and suppresses inflammatory pathways and genes associated with HF and aging. Relaxin's suppression of inflammation and fibrosis supports its potential as a therapy for cardiovascular and inflammation-related diseases, such as HF, AF and diabetes.
Topics: Age Factors; Aging; Animals; Atrial Fibrillation; Biomarkers; Cohort Studies; Disease Models, Animal; Female; Fluorescent Antibody Technique; Heart; Heart Failure; Humans; Inflammation; Macrophages; Male; Rats; Rats, Inbred F344; Relaxin; Sequence Analysis, RNA; Sex Factors
PubMed: 29346407
DOI: 10.1371/journal.pone.0190935 -
Journal of Clinical Hypertension... Jan 2019Masked hypertension (HTN) and white coat hypertension represent two reverse forms of clinical HTN with questionable prognostic significance. Recent evidence supports... (Comparative Study)
Comparative Study
Masked hypertension (HTN) and white coat hypertension represent two reverse forms of clinical HTN with questionable prognostic significance. Recent evidence supports that low apelin and relaxin plasma levels contribute to vascular damage accelerating atherogenesis and predisposing to HTN and cardiovascular (CV) events. The aim of this study was to compare apelin and relaxin plasma levels between patients with masked hypertension (MH) and those with white coat HTN (WCH). Overall, 130 patients not receiving antihypertensive therapy were studied. All patients underwent 24-hour ambulatory BP monitoring (ABPM) and office BP measurements. Plasma apelin and relaxin levels were measured by ELISA method. According to BP recordings, 24 subjects had MH (group A) and 32 had WCH (group B). Apelin (200 ± 111 pg/mL vs 305 ± 127 pg/mL, P < 0.01) and relaxin (35.2 ± 6.7 pg/mL vs 46.8 ± 23.6 pg/mL, P < 0.01) plasma levels were significantly lower in patients with MH compared to those with WCH, respectively. In conclusion, our findings showed that patients with MH had significantly lower apelin and relaxin levels compared to those with WCH. This observation implies an additional prognostic role for adipokines supporting the concept that MH is closer to essential HTN whereas WCH is a more benign condition.
Topics: Adipokines; Adult; Apelin; Atherosclerosis; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Cross-Sectional Studies; Essential Hypertension; Female; Humans; Male; Masked Hypertension; Middle Aged; Prevalence; Prognosis; Relaxin; Risk Factors; White Coat Hypertension
PubMed: 30525273
DOI: 10.1111/jch.13449 -
International Journal of Cancer Nov 2015Targeting the androgen signalling pathway has long been the hallmark of anti-hormonal therapy for prostate cancer. However, development of androgen-independent prostate... (Review)
Review
Targeting the androgen signalling pathway has long been the hallmark of anti-hormonal therapy for prostate cancer. However, development of androgen-independent prostate cancer is an inevitable outcome to therapies targeting this pathway, in part, owing to the shift from cancer dependence on androgen signalling for growth in favor of augmentation of other cellular pathways that provide proliferation-, survival- and angiogenesis-promoting signals. This review focuses on the role of the hormone relaxin in the development and progression of prostate cancer, prior to and after the onset of androgen independence, as well as its role in cancers of other reproductive tissues. As the body of literature expands, examining relaxin expression in cancerous tissues and its role in a growing number of in vitro and in vivo cancer models, our understanding of the important involvement of this hormone in cancer biology is becoming clearer. Specifically, the pleiotropic functions of relaxin affecting cell growth, angiogenesis, blood flow, cell migration and extracellular matrix remodeling are examined in the context of cancer progression. The interactions and intercepts of the intracellular signalling pathways of relaxin with the androgen pathway are explored in the context of progression of castration-resistant and androgen-independent prostate cancers. We provide an overview of current anti-hormonal therapeutic treatment options for prostate cancer and delve into therapeutic approaches and development of agents aimed at specifically antagonizing relaxin signalling to curb tumor growth. We also discuss the rationale and challenges utilizing such agents as novel anti-hormonals in the clinic, and their potential to supplement current therapeutic modalities.
Topics: Animals; Antineoplastic Agents; Disease Progression; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Relaxin; Signal Transduction
PubMed: 25043063
DOI: 10.1002/ijc.29079 -
The New England Journal of Medicine Aug 2019Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure.
METHODS
In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days.
RESULTS
A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups.
CONCLUSIONS
In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).
Topics: Acute Disease; Aged; Blood Pressure; Cardiovascular Diseases; Disease Progression; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Incidence; Infusions, Intravenous; Male; Recombinant Proteins; Relaxin; Treatment Failure; Vasodilator Agents
PubMed: 31433919
DOI: 10.1056/NEJMoa1801291 -
Nature Communications Jan 2023Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides,...
Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4-G protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053. The B chain of INSL5 adopts a single α-helix that penetrates into the orthosteric pocket, while the A chain sits above the orthosteric pocket, revealing a peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. Our findings not only provide insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, but also expand the knowledge of signaling mechanisms in the insulin superfamily.
Topics: Humans; Relaxin; Ligands; Cryoelectron Microscopy; Insulin; Receptors, G-Protein-Coupled; Signal Transduction; Receptors, Peptide
PubMed: 36717591
DOI: 10.1038/s41467-023-36182-z -
Journal of Medicinal Chemistry Jun 2022The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To...
The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 () that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.
Topics: Animals; Insulin; Ligands; Rats; Receptors, G-Protein-Coupled; Receptors, Peptide; Relaxin
PubMed: 35594150
DOI: 10.1021/acs.jmedchem.2c00508 -
Computational and Mathematical Methods... 2022This study is aimed at investigating whether relaxin-3 exhibits protective effects against cardiomyopathy in diabetic rats by suppressing ERS.
BACKGROUND
This study is aimed at investigating whether relaxin-3 exhibits protective effects against cardiomyopathy in diabetic rats by suppressing ERS.
METHODS
Eighty male SD rats were randomly divided into two groups: controls ( = 20) and diabetes ( = 60). The streptozotocin-treated rats were randomly divided into three groups: diabetic group (DM), low-dose relaxin-3 group (0.2 g/kg/d), and high-dose relaxin-3 group (2 g/kg/d). The myocardial tissues and collagen fiber were observed by hematoxylin and eosin (H&E) and Masson staining. Serum brain natriuretic peptide (BNP), troponin (TNI), myoglobin, interleukin (IL-17), interleukin (IL)-1, and tumor necrosis factor (TNF)- were determined by ELISA. The protein expression of glucose regulatory protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the heart tissue of each group was detected by Western blot analysis.
RESULTS
(1) HE and Masson staining indicated that relaxin-3 could attenuate myocardial lesions and myocardial collagen volume fraction. (2) BNP, TnI, and myoglobin in the DM group at four and eight weeks were significantly higher than in the controls ( < 0.01). The relaxin-3-treated groups showed significantly reduced serum BNP, TnI, and myoglobin levels compared with the DM group ( < 0.05). (3) IL-17, IL-1, and TNF- levels in the DM rats at 4 weeks were higher than in the controls ( < 0.05). Low or high dose of relaxin-3-treated groups showed reduced serum IL-17 and TNF- levels compared with the DM group at four and eight weeks ( < 0.05). (4) CHOP and GRP78 protein expression was increased in the DM group at four and eight weeks compared with the controls ( < 0.01), and small and large doses of relaxin-3 significantly reduced GRP78 and CHOP protein expression.
CONCLUSIONS
Exogenous relaxin-3 ameliorates diabetic cardiomyopathy by inhibiting ERS in diabetic rats.
Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Endoplasmic Reticulum Stress; Eosine Yellowish-(YS); Glucose; Hematoxylin; Interleukin-17; Male; Myoglobin; Natriuretic Peptide, Brain; Rats; Rats, Sprague-Dawley; Relaxin; Streptozocin; Troponin; Tumor Necrosis Factor-alpha
PubMed: 36203531
DOI: 10.1155/2022/9380283