The pregnancy hormone relaxin is a player in human heart failure

Dschietzig, Thomas; Richter, Christoph; Bartsch, Cornelia; Laule, Michael; Armbruster, Franz Paul; Baumann, Gert; Stangl, Karl

doi:10.1096/fj.01-0070com

Cited by 194 publications

(225 citation statements)

References 28 publications

Supporting

Mentioning

212

Contrasting

Unclassified

Order By: Relevance

“…Detection of immunoreactive RLN2 in the human thyroid tissue sections was performed with two previously characterized rabbit polyclonal antibodies against RLN2. One polyclonal antiserum against RLN2 was from Immunodiagnostik (Bensheim, Germany) 21 and was diluted 1:300 in blocking buffer overnight at 4°C. Serial sections were also immunostained with the R6 rabbit anti-porcine relaxin antiserum (generously provided by Prof. Bernhard Steinetz, Nelson Institute of Environmental Medicine, New York University Medical Center, Tuxedo, NY) at a dilution of 1:800 in blocking buffer at 4°C overnight.…”

Section: Immunohistochemistry and Evaluationmentioning

confidence: 99%

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Hombach‐Klonisch

Białek

Trojanowicz

et al. 2006

The American Journal of Pathology

102

View full text Add to dashboard Cite

The role of members of the insulin-like superfamily in human thyroid carcinoma is primarily unknown. Here we demonstrate the presence of RLN2 relaxin and relaxin receptor LGR7 in human papillary, follicular, and undifferentiated anaplastic thyroid carcinoma suggesting a specific involvement of relaxin-LGR7 signaling in thyroid carcinoma. Stable transfectants of the LGR7-positive human follicular thyroid carcinoma cell lines FTC-133 and FTC-238 that secrete bioactive proRLN2 revealed this hormone to act as a multifunctional endocrine factor in thyroid carcinoma cells. Although RLN2 did not act as a mitogen, it acted as an autocrine/paracrine factor and significantly increased anchorage-independent growth and thyroid carcinoma cell motility and invasiveness through elastin matrices. In recent years, the multifunctional peptide hormone relaxin has been identified as an important endocrine player in the reproductive tract, cardiovascular/neural systems, and oncology.1,2 The thyroid was once considered to be a relaxin target tissue with relaxin reported to increase thyroid weight, radioactive iodine uptake, and protein-bound iodination in rats.3,4 Likely because of the crude relaxin preparations used at the time, these results could not be confirmed. 5 No further investigations were reported thereafter using highly purified relaxin preparations to validate a potential role of relaxin in thyroid tissues and thyroid cell lines. Some 40 years later, the discovery of the G-protein-coupled relaxin-like receptors LGR7 and LGR8 revealed the presence of transcripts for both LGR7 (relaxin receptor) and LGR8 (INSL3/relaxin receptor) in the thyroid gland. 6 -8 Relaxin and the relaxin-like INSL3 have been shown to activate cAMP-dependent signaling pathways by binding to either LGR7 or LGR8. 8 -12 We recently demonstrated the expression and regulation of INSL3 and LGR8 transcripts in human thyroid carcinoma cell lines, identifying hyper-and neoplastic human thyrocytes as a new source and target of the actions of INSL3 and a novel INSL3 splice variant. 8,13 Although still primarily undefined, relaxin appears to have oncogenic potential in various organs and tissues, including the human thyroid.14 -17 Relaxin affects proliferation and differentiation of MCF-7 human carcinoma cells in a concentration-dependent manner 18 and can modify the extracellular matrix by affecting the expresSupported by the Deutsche Forschungsgemeinschaft (grants KL1249/5-1

show abstract

Section: Immunohistochemistry and Evaluationmentioning

confidence: 99%

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Hombach‐Klonisch

Białek

Trojanowicz

et al. 2006

The American Journal of Pathology

102

View full text Add to dashboard Cite

show abstract

“…This causes systemic and renal vasodilation, increased arterial compliance, and other vascular changes. These findings have led to current clinical trial evaluation of relaxin as drug for the treatment of patients with acute heart failure (AHF) 6 (4,5). Furthermore, the matrix remodeling actions of H2 relaxin have enhanced its reputation as a rapidly acting but safe antifibrotic agent, which has been further supported by its ability to successfully inhibit and/or reverse fibrosis in every preclinical model of experimental disease evaluated to date (6,7).…”

mentioning

confidence: 99%

The Minimal Active Structure of Human Relaxin-2

Hossain

Rosengren

Samuel

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

H2 relaxin is a peptide hormone associated with a number of therapeutically relevant physiological effects, including regulation of collagen metabolism and multiple vascular control pathways. It is currently in phase III clinical trials for the treatment of acute heart failure due to its ability to induce vasodilation and influence renal function. It comprises 53 amino acids and is characterized by two separate polypeptide chains (A-B) that are cross-linked by three disulfide bonds. This size and complex structure represents a considerable challenge for the chemical synthesis of H2 relaxin, a major limiting factor for the exploration of modifications and derivatizations of this peptide, to optimize effect and drug-like characteristics. To address this issue, we describe the solid phase peptide synthesis and structural and functional evaluation of 24 analogues of H2 relaxin with truncations at the termini of its peptide chains. We show that it is possible to significantly truncate both the N and C termini of the B-chain while still retaining potent biological activity. This suggests that these regions are not critical for interactions with the H2 relaxin receptor, RXFP1. In contrast, truncations do reduce the activity of H2 relaxin for the related receptor RXFP2 by improving RXFP1 selectivity. In addition to new mechanistic insights into the function of H2 relaxin, this study identifies a critical active core with 38 amino acids. This minimized core shows similar antifibrotic activity as native H2 relaxin when tested in human BJ3 cells and thus represents an attractive receptor-selective lead for the development of novel relaxin therapeutics.Human relaxin-2 or H2 relaxin is a peptide hormone with multiple pleiotropic actions (1). Initially thought to be only a reproductive hormone involved in facilitating delivery of the young, more recent studies have demonstrated that H2 relaxin plays a key role in inflammatory and matrix remodeling processes and possesses potent vasodilatory, angiogenic, and other cardioprotective actions (2). The vasodilatory effects of H2 relaxin are thought to involve promotion of nitric oxide and the gelatinases, matrix metalloproteinase-2 and matrix metalloproteinase-9, in addition to antagonism of the vasoconstricting actions of endothelin-1 and angiotensin II (3). This causes systemic and renal vasodilation, increased arterial compliance, and other vascular changes. These findings have led to current clinical trial evaluation of relaxin as drug for the treatment of patients with acute heart failure (AHF) 6 (4, 5). Furthermore, the matrix remodeling actions of H2 relaxin have enhanced its reputation as a rapidly acting but safe antifibrotic agent, which has been further supported by its ability to successfully inhibit and/or reverse fibrosis in every preclinical model of experimental disease evaluated to date (6, 7).All of the above actions of H2 relaxin are thought to be mediated through its native receptor RXFP1 (originally named LGR7), which is a leucine-rich repeat containing G-prote...

show abstract

“…In support of that notion (compensatory increased synthesis of relaxin in the course of chronic heart damage in uremic patients with ESKD) is the observation that plasma relaxin and left ventricular relaxin mRNA are elevated in patient with chronic heart failure. 2 Adding BNP, a parameter that describes heart failure in patients on hemodialysis, 13 to the Cox regression Relaxin, pg/mL 33.8Ϯ39.3…”

Section: Discussionmentioning

confidence: 99%

“…Patients with chronic heart failure have increased myocardial relaxin gene expression and elevated plasma relaxin concentrations. 2 Relaxin stimulates cardiac ANP secretion 3 and increases coronary blood flow through a nitric oxide-mediated mechanism. 3 It was furthermore shown that relaxin is a vasodilator of small systemic resistance arteries.…”

mentioning

confidence: 99%

Relaxin Is an Independent Risk Factor Predicting Death in Male Patients With End-Stage Kidney Disease

et al. 2004

View full text Add to dashboard Cite

Background-Patients with end-stage kidney disease (ESKD) have a reduced life expectancy mainly as the result of cardiovascular diseases. Relaxin has been implicated in the pathogenesis of cardiovascular diseases. We analyzed the impact of relaxin on death in patients with ESKD. Methods and Results-Patients (n ϭ245; 122 women, 123 men) on long-term hemodialysis were followed for 1140 days for death. Blood samples for analysis of relaxin, C-reactive protein, Troponin T, cholesterol, HDL, brain natriuretic peptide, and albumin were taken at study entry. Survival was compared by the Kaplan-Meier method and Cox regression analysis. One hundred seven patients died during the observation period; 66 died of cardiovascular diseases and 28 died of infectious diseases. Elevated serum relaxin concentrations (greater than median) predicted death in male but not in female patients with ESKD: All-cause death (men: relative risk, 2.63; 95% CI, njections of serum from pregnant rabbits induced relaxation of the interpubic ligament of guinea pigs. 1 The hormone responsible for this action was named relaxin. Corpus luteum, decidua, and placenta secrete this hormone during pregnancy. Relaxin has many important roles in pregnancy, including softening effects on connective tissue, reducing uterine contractility, and control of mammary gland growth and differentiation. 1 Recently, however, it was recognized that relaxin also plays a role in the cardiovascular system. Patients with chronic heart failure have increased myocardial relaxin gene expression and elevated plasma relaxin concentrations. 2 Relaxin stimulates cardiac ANP secretion 3 and increases coronary blood flow through a nitric oxide-mediated mechanism. 3 It was furthermore shown that relaxin is a vasodilator of small systemic resistance arteries. 4 Relaxin is also involved in the regulation of cardiac 5 and renal 6 collagen synthesis.We analyzed whether relaxin is a mortality risk factor in patients with end-stage kidney disease (ESKD). Patients with ESKD have a substantially reduced life expectancy. The mortality risk is about 50% higher in elderly patients with ESKD and even much more in younger patients with ESDK as compared with age-matched persons without renal disease. 7,8 MethodsThe 245 patients (122 women, 123 men) were recruited from two dialysis centers (KfH Dialysezentrum-Neukölln, Berlin, and KfH Dialysezentrum-Moabit, Berlin). The patients are dialyzed at least 3 times weekly in 4-to 6-hour sessions, sufficient to provide an urea kinetic on dialysis (KT/V) of at least 1.3. The included patients represent all patients being on stable hemodialysis in these centers without actual health problems. All patients were included in the study in March 2000 and followed for 1140 days. The following patients characteristics were documented: age, gender, body mass index, cause of ESKD, time on dialysis, diabetes, hypertension, and coronary heart disease (patients with a history of myocardial infarction, coronary heart disease confirmed by heart catheterization, or typical ...

show abstract

The pregnancy hormone relaxin is a player in human heart failure

Cited by 194 publications

References 28 publications

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

The Minimal Active Structure of Human Relaxin-2

Relaxin Is an Independent Risk Factor Predicting Death in Male Patients With End-Stage Kidney Disease

Contact Info

Product

Resources

About