Relaxin inhibits early steps in vascular inflammation

Brecht, Anna; Bartsch, Cornelia; Baumann, Gert; Stangl, Karl; Dschietzig, Thomas

doi:10.1016/j.regpep.2010.09.001

Cited by 55 publications

(44 citation statements)

References 37 publications

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“…46,47 In conclusion, another potentially novel feature of relaxin is its ability to mobilize and activate BMDECs without being proinflammatory; indeed, the hormone may be anti-inflammatory. 50 This would make relaxin the only cytokine known to positively impact BMDECs number and function without being proinflammatory, which may offer a distinct advantage for relaxin as a potent therapeutic in cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice

Segal¹,

Sautina²,

Li³

et al. 2012

Blood

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The ovarian peptide hormone, relaxin, circulates during pregnancy, contributing to profound maternal vasodilation through endothelial and nitric oxide (NO)-dependent mechanisms. Circulating numbers of bone marrow-derived endothelial cells (BMDECs), which facilitate angiogenesis and contribute to repair of vascular endothelium, increase during pregnancy. Thus, we hypothesized that relaxin enhances BMDEC NO production, circulating numbers, and function. Recombinant human relaxin-2 (rhRLX) stimulated PI3K/Akt B-dependent NO production in human BMDECs within minutes, and activated BMDEC migration that was inhibited by L-N G -nitroarginine methyl ester. In BMDECs isolated from relaxin/ insulin-like family peptide receptor 2 gene (Rxfp2) knockout and wild-type mice, but not Rxfp1 knockout mice, rhRLX rapidly increased NO production. Similarly, rhRLX increased circulating BMDEC number in Rxfp2 knockout and wild-type mice, but not Rxfp1 knockout mice as assessed by colony formation and flow cytometry. IntroductionDramatic changes in systemic and renal hemodynamics occur during pregnancy. There is a marked decrease in systemic vascular resistance and reciprocal increases in cardiac output and global arterial compliance, accompanied by a modest decline in mean arterial pressure. The renal circulation participates in this maternal vasodilatory response; consequently, renal plasma flow and glomerular filtration rate rise by 80% and 50%, respectively. Although understanding of the mechanisms underlying these maternal adaptations to pregnancy is incomplete, there is increasing evidence that the ovarian peptide hormone relaxin plays a key role. 1 Originally isolated from the ovary by Hisaw, 2 relaxin was named for its ability to relax the pubis symphysis in some species. In nonhuman primates, it was subsequently shown by the same investigators to cause morphologic changes in endothelial cells of endometrial blood vessels consistent with hypertrophy and hyperplasia, and enlargement of arterioles and capillaries. 3 Humans have 3 relaxin genes, designated relaxin-1, -2, and -3. 4 Rats and mice each have 2 relaxin genes designated relaxin-1 and -3. Human relaxin-2, as well as rat and mouse relaxin-1 gene products, are true orthologs, insofar as they are secreted by the corpus luteum during pregnancy and circulate. Humans, rats, and mice have 1 relaxin receptor, the LGR7 (leucine rich repeat-containing G protein coupled) receptor recently renamed relaxin/insulin-like family peptide 1 receptor, RXFP1. Although human relaxin may also bind to the LGR8 receptor (RXFP2), albeit with reduced affinity, 5 the preferred ligand for RXFP2 is insulin-like 3 (INSL3). Recently, 2 new receptors have been described for relaxin-3, GPCR135 and 142, 6 although GPCR142 is a pseudogene in rats.Infusion of recombinant human relaxin-2 (rhRLX) in nonpregnant conscious female and male rats significantly decreases renal and systemic vascular resistances, and increases cardiac output, renal blood flow, glomerular filtration, and global arterial compliance, ...

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Section: Discussionmentioning

confidence: 99%

Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice

Segal¹,

Sautina²,

Li³

et al. 2012

Blood

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show abstract

“…This vascular protection is further complemented by NO-mediated inhibition of platelet and neutrophil activation (Bani et al, 1995a,b;Masini et al, 2004). Relaxin also attenuates VCAM-1 and MCP-1 stimulation that mediate the initial monocyte-endothelium contact and are both key events in early vascular inflammation (Brecht et al, 2011).…”

Section: Physiologic Roles Of Relaxin Family Peptide Receptors Andmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

Halls¹,

Bathgate²,

Sutton³

et al. 2015

Pharmacol Rev

122

118

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“…Relaxin was shown to promote vasodilation, cardioprotection, antifibrotic wound healing, and angiogenesis (Brecht et al ., 2011; Conrad and Shroff, 2011; Du et al ., 2010). In various tumors, the RLN2‐RXFP1 has emerged as an important ligand–receptor system involved in controlling growth, migration/tissue invasion, angiogenesis, and metastasis (Klonisch et al ., 2007).…”

Section: Introductionmentioning

confidence: 99%

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

et al. 2018

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The C1q/TNF‐related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein‐coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8‐RXFP1 ligand–receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1‐STAT3 signaling cascade in GBM cells. We identified N‐methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8‐RXFP1‐STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double‐strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8‐induced RXFP1 activation caused an increase in cellular protein levels of the anti‐apoptotic Bcl members and STAT3 targets Bcl‐2 and Bcl‐XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8‐RXFP1 ligand–receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8‐RXFP1‐STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.

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Relaxin inhibits early steps in vascular inflammation

Cited by 55 publications

References 37 publications

Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice

Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

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