Serelaxin treatment promotes adaptive hypertrophy but does not prevent heart failure in experimental peripartum cardiomyopathy

Nonhoff, Justus; Ricke‐Hoch, Melanie; Mueller, Mirco; Stapel, Britta; Pfeffer, Tobias Jonathan; Kasten, Martina; Scherr, Michaela; Kaisenberg, Constantin von; Bauersachs, Johann; Haghikia, Arash; Hilfiker‐Kleiner, Denise

doi:10.1093/cvr/cvw245

Cited by 14 publications

(9 citation statements)

References 39 publications

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“…Among the differentially regulated pathways, activity of the NF‐kB signaling pathway differed the most between the two groups (Tables and ). Several lines of evidence suggest that NF‐kB plays a pivotal role in myocardial remodeling by regulating inflammation and cell death; however, additional pathways identified in our analysis, such as the Gαq and prolactin pathways (Tables and ), are also involved in such remodeling, especially in cardiac hypertrophy . Our bioinformatics analysis and in vivo experiments (Figs and ), together with the previous finding that NF‐kB signaling elicits both cardioprotective and cardiotoxic effects , suggest that NF‐kB signaling is one of the most important pathways underlying myocardial remodeling in response to anesthesia.…”

Section: Discussionsupporting

confidence: 58%

NF‐kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol

et al. 2020

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Both inhalational and intravenous anesthetics affect myocardial remodeling, but the precise effect of each anesthetic on molecular signaling in myocardial remodeling is unknown. Here, we performed in silico analysis to investigate signaling alterations in cardiomyocytes induced by inhalational [sevoflurane (Sevo)] and intravenous [propofol (Prop)] anesthetics. Bioinformatics analysis revealed that nuclear factor‐kappa B (NF‐kB) signaling was inhibited by Sevo and promoted by Prop. Moreover, nuclear accumulation of p65 and transcription of NF‐kB‐regulated genes were suppressed in Sevo‐administered mice, suggesting that Sevo inhibits the NF‐kB signaling pathway. Our data demonstrate that NF‐kB signaling is inhibited by Sevo and promoted by Prop. As NF‐kB signaling plays an important role in myocardial remodeling, our results suggest that anesthetics may affect myocardial remodeling through NF‐kB.

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Section: Discussionsupporting

confidence: 58%

NF‐kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol

et al. 2020

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“…For instance, relaxin-2 has been shown to potently attenuate cardiac fibrosis, as evidenced by the cardiac fibrotic phenotype in relaxin-2 deficient mice and inhibition of established cardiac fibrosis following relaxin treatment (3) (10). In the animal models of ischemia and reperfusion, relaxin-2 has been reported to reduce myocardial injury and preserve ventricular function (11) (12). Of the three known relaxin genes, Relaxin-2 is the only relaxin known to circulate in the blood.…”

mentioning

confidence: 99%

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

You

Guo

Fang

et al. 2018

Journal of Biological Chemistry

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The relaxin family peptides have been shown to exert several beneficial effects on the heart, including anti-apoptosis, anti-fibrosis, and antihypertrophy activity. Understanding their regulation might provide new opportunities for therapeutic interventions, but the molecular mechanism(s) coordinating relaxin expression in the heart remain largely obscured. Previous work demonstrated a role for the orphan nuclear receptor Nur77 in regulating cardiomyocyte apoptosis. We therefore investigated Nur77 in the hopes of identifying novel relaxin regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) data indicated that ectopic expression of orphan nuclear receptor Nur77 markedly increased the expression of latexin-3 (RLN3), but not relaxin-1 (RLN1), in neonatal rat ventricular cardiomyocytes (NRVMs). Furthermore, we found that the beta-adrenergic agonist isoproterenol (ISO) markedly stimulated RLN3 expression, and this stimulation was significantly attenuated in Nur77 knockdown cardiomyocytes and Nur77 knockout hearts. We showed that Nur77 significantly increased RLN3 promoter activity via specific binding to the RLN3 promoter, as demonstrated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Furthermore, we found that Nur77 overexpression potently inhibited ISO-induced cardiomyocyte apoptosis, while this protective effect was significantly attenuated in RLN3 knockdown cardiomyocytes, suggesting that Nur77-induced RLN3 expression is an important mediator for the suppression of cardiomyocyte apoptosis. These findings show that Nur77 regulates RLN3 expression, therefore suppressing apoptosis in the heart, and suggest that activation of Nur77 may represent a useful therapeutic strategy for inhibition of cardiac fibrosis and heart failure. Upregulation of Relaxin-3 by Nur77 2The relaxin peptide family in humans consists of seven members, relaxin-1 (H1 relaxin), relaxin-2 (H2 relaxin), relaxin-3 (H3 relaxin) and insulin-like (INSL) peptides (1). Like insulin, relaxin consists of two peptide chains, A and B, covalently linked by disulfide bonds. Through binding to the relaxin family peptide (RXFP) receptors, the relaxin peptide has been shown to initiate a wide range of biological effects in various systems, including regulation of cell survival, proliferation, vessel relaxation, inflammation, and fibrosis (1) (2) (3) (4). Humans (and higher primates) have three relaxin genes, designated H1, H2, and H3 relaxin, while rodents have two genes, relaxin (equivalent to H2 relaxin) and relaxin-3 (equivalent to H3 relaxin) (5). H2 relaxin is the major source of circulating relaxin. Four relaxin family peptide receptors (RXFP1-4) have been identified (6) (7). H2 relaxin is a ligand for receptors RXFP1 and RXFP2, whereas H3 relaxin is the ligand for RXFP3, but also crossreacts with RXFP1 and RXFP4 (6). Despite the physiological significance of relaxin in the reproductive and central nervous systems, the cardiovascular effects of relaxin have...

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“…However, none of these assay methods have published details regarding sensitivity and reliability. Nevertheless, some of them have been successfully used for clinical studies with different questions, e.g., birthweight regulation and other pregnancy complications (17,18,30), peripartum cardiomyopathy (31), vascular dysfunction in type 1 diabetes (32), and cirrhosis (33).…”

Section: Discussionmentioning

confidence: 99%

Quantification of Relaxin-2 Connecting Peptide (Pro-RLX2) in Human Blood Samples

Rehfeldt¹,

Sparwaßer²,

Funk³

et al. 2017

The Journal of Applied Laboratory Medicine

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Background: The peptide hormone relaxin-2 is implicated in diverse physiological and pathophysiological processes. Several assays are available for quantification of human relaxin-2, but because stability of the mature peptide in serum is limited, measurement of the more stable connecting peptide (pro-RLX2) might be beneficial. Methods: Pro-RLX2 was measured in a sandwich immunoluminometric assay using 2 monoclonal antibodies. The concentration of pro-RLX2 was detected in healthy pregnant (n = 100) and healthy male and nonpregnant female (n = 81) subjects and compared with the concentration of mature relaxin-2 in a subset of samples. Results: The pro-RLX2 immunoassay has an analytical and functional assay sensitivity (FAS) of 1.59 pmol/L and 1.7 pmol/L, respectively. The analyte is stable in EDTA plasma samples for 8 days at room temperature, dilutes in a linear fashion, and recovery was 103%. The assay system is not biased by common interfering substances. Measurement of 80% of plasma samples from healthy males and females is below the FAS {median 1.49 pmol/L [interquartile range (IQR) of 0.925-2.14 pmol/L]}, and no concentration difference between male and nonpregnant female plasma samples was observed. The median plasma concentration in healthy pregnant women is increased up to 562 pmol/L (IQR 341-789 pmol/L). During pregnancy, pro-RLX2 concentrations decrease with increasing gestation. The correlation coefficient with the R&D assay for mature relaxin-2 was 0.96 (P < 0.0001). Conclusion: Pro-RLX2 is stable in plasma of healthy individuals. Although samples of pregnant women are reliably measurable, most samples from healthy nonpregnant women and men are below the detection limit. Determination of pro-RLX2 concentrations might indicate rate of synthesis of relaxin-2 during pregnancy and therapeutic application of recombinant relaxin (Serelaxin). IMPACT STATEMENT We described a highly reliable immunoassay for quantification of the human relaxin-2 connecting peptide (pro-RLX2), which is more sensitive than established methods for quantification of the mature peptide. As relaxin-2 is known to regulate cardiovascular adaptation to pregnancy, quantification of pro-RLX2 might be helpful in the diagnosis, monitoring, and prognosis of preeclampsia and other pregnancy-related complications. Furthermore, because recombinant relaxin-2 improves multiple-organ function, endogenous relaxin might influence other organs as well, and pathologies might be associated with changed endogenous expression. Thus, quantification of pro-RLX2 might be interesting in different pathologies in nonpregnant women.

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Serelaxin treatment promotes adaptive hypertrophy but does not prevent heart failure in experimental peripartum cardiomyopathy

Cited by 14 publications

References 39 publications

NF‐kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol

NF‐kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

Quantification of Relaxin-2 Connecting Peptide (Pro-RLX2) in Human Blood Samples

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