Relaxin

Relaxin is a protein hormone of about 6000 Da[1] first described in 1926 by Frederick Hisaw.[2][3]

For the Miles Davis album, see Relaxin' with the Miles Davis Quintet.
Relaxin 1
Identifiers
SymbolRLN1
Alt. symbolsH1
NCBI gene6013
HGNC10026
OMIM179730
RefSeqNM_006911
UniProtP04808
Other data
LocusChr. 9 qter-q12
Relaxin 2
Identifiers
SymbolRLN2
Alt. symbolsH2, RLXH2, bA12D24.1.1, bA12D24.1.2
NCBI gene6019
HGNC10027
OMIM179740
PDB6RLX
RefSeqNM_134441
UniProtP04090
Other data
LocusChr. 9 qter-q12
Relaxin 3
Identifiers
SymbolRLN3
Alt. symbolsZINS4, RXN3, H3
NCBI gene117579
HGNC17135
OMIM606855
RefSeqNM_080864
UniProtQ8WXF3
Other data
LocusChr. 19 p13.3

The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1 (RLN1), 2 (RLN2) and 3 (RLN3), and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised.[4]

Synthesis

In the female, it is produced by the corpus luteum of the ovary, the breast and, during pregnancy, also by the placenta, chorion, and decidua.

In the male, it is produced in the prostate and is present in human semen.[5]

Structure
See also: Insulin/IGF/Relaxin family

Structurally, relaxin is a heterodimer of two peptide chains of 24 and 29 amino acids linked by disulfide bridges, and it appears related to insulin.[6]

Relaxin is produced from its prohormone, "prorelaxin", by splitting off one additional peptide chain reaction.

Function

In humans

In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females.[1] Relaxin levels rise to a peak within approximately 14 days of ovulation, and then decline in the absence of pregnancy, resulting in menstruation.[7] Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation.[8] During the first trimester of pregnancy, levels rise and additional relaxin is produced by the decidua. Relaxin's peak is reached during the first trimester (14-weeks) and at delivery. Relaxin mediates the hemodynamic changes that occur during pregnancy, such as increased cardiac output, increased renal blood flow, and increased arterial compliance. It also relaxes other pelvic ligaments.[9] It is believed to soften the pubic symphysis.

In males, relaxin enhances motility of sperm in semen.[10]

In the cardiovascular system, relaxin works mainly by activating the nitric oxide pathway. Other mechanisms include activation of NFκB leading to vascular endothelial growth factor (VEGF) and matrix metalloproteinases transcription.[11]

Relaxin has been shown to relax vascular smooth muscle cells and increase nitric oxide production in rat endothelial cells, thus playing a role in regulation of cardiovascular function by dilating systemic resistance arteries.[11] Relaxin increases the rate and force of cardiac contraction in rat models.[12] Via upregulation of VEGF, relaxin plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.[12]

In other animals

In animals, relaxin widens the pubic bone and facilitates labor; it also softens the cervix (cervical ripening), and relaxes the uterine musculature. Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin may affect collagen metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing matrix metalloproteinases.[13] It also enhances angiogenesis and is a potent renal vasodilator.

In the mouse model, relaxin has been found to promote maturation of cardiomyocytes.[12]

Several animal studies have found relaxin to have a cardioprotective function against ischaemia and reperfusion injury, by reducing cellular damage, via anti-apoptotic and anti-inflammatory effects. Relaxin has been shown to reduce cardiac fibrosis in animal models by inhibiting cardiac fibroblasts secreting collagen and stimulating matrix metalloproteinase.[12][11]

In the European rabbit (Oryctolagus cuniculus), relaxin is associated with squamous differentiation and is expressed in tracheobronchial epithelial cells as opposed to being involved with reproduction.[14]

In horses (Equus caballus), relaxin is also an important hormone involved in pregnancy, however, before pregnancy occurs, relaxin is expressed by ovarian structures during the oestrous cycle.[15] Prior to ovulation, relaxin will be produced by ovarian stromal cells, which will promote secretion of gelatinases and tissue inhibitors of metalloproteinases. These enzymes will then aid the process of ovulation, which will lead to the release of a developed follicle into the fallopian tube.[15] Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size.[15] During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF.[15][16] This will allow the endometrium to prepare for implantation. In horses alone, the embryo in the uterus will express relaxin mRNA at least 8 days after ovulation. Then as the conceptus develops expression will increase, which is likely to promote embryo development.[15]

In addition to relaxin production by the horse embryo, the maternal placenta is the main source of relaxin production, whereas in most animals the main source of relaxin is the corpus luteum.[15] Placental trophoblast cells produce relaxin, however, the size of the placenta does not determine the level of relaxin production. This is seen because different breeds of horses show different relaxin levels.[17] From 80 day of gestation onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation.[17][18] Moreover, the pattern of relaxin expression will follow the expression of oestrogen, however, there is not yet a known link between these two hormones.[18] During labour, there is a spike in relaxin 3–4 hours before delivery, which is involved in myometrial relaxation and softening of the pelvic ligaments to aid preparation of the birth canal for the delivery of the horse foetus.[15][17] Following birth, the levels of relaxin will gradually decrease if the placenta is also delivered, however, if the placenta is retained in the mare then the levels will remain high.[17] In addition, if the mare undergoes an abortion then the relaxin levels will decline as the placenta ceases to function.[17]

Receptors

Relaxin interacts with the relaxin receptor LGR7 (RXFP1) and LGR8 (RXFP2), which belong to the G protein-coupled receptor superfamily.[19] They contain a heptahelical transmembrane domain and a large glycosylated ectodomain, distantly related to the receptors for the glycoproteohormones, such as the LH-receptor or FSH-receptor.

Relaxin receptors have been found in the heart, smooth muscle, the connective tissue, and central and autonomous nervous system.

Disorders

Women who have been on relaxin treatment during unrelated clinical trials have experienced heavier bleeding during their menstrural cycle, suggesting that relaxin levels could play a role in abnormal uterine bleeding.[20] However, more research needs to go into this to confirm relaxin as a direct cause.

A lower expression of relaxin has been found amongst women who have endometriosis. The research in this area is limited and more studying of relaxin's contribution could contribute greatly to the understanding of endometriosis.[20]

Specific disorders related to relaxin have not been heavily described, yet a link to scleroderma and fibromyalgia has also been suggested.[21]

Pregnancy

It is possible that relaxin in the placenta could be a contributing factor to inducing labour in humans and therefore serum relaxin levels during pregnancy have been linked to premature birth.[20]

Pharmacological targets

A recombinant form of human relaxin-2 has been developed as investigational drug RLX030 (serelaxin).

It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders.[20]

Evolution

Relaxin 1 and relaxin 2 arose from the duplication of a proto-RLN gene between 44.2 and 29.6 million years ago in the last common ancestor of catarrhine primates.[22] The duplication that led to RLN1 and RLN2 is thought to have been a result of positive selection and convergent evolution at the nucleotide level between the relaxin gene in New World monkeys and the RLN1 gene in apes.[22] As a result, Old World monkeys, a group that includes the subfamilies colobines and cercopithecines, have lost the RLN1 paralog, but apes have retained both the RLN1 and the RLN2 genes;[22] Lawrence and Cords, 2012).

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See also

References
  1. Bani D (January 1997). "Relaxin: a pleiotropic hormone". General Pharmacology. 28 (1): 13–22. doi:10.1016/s0306-3623(96)00171-1. PMID 9112071.
  2. "If a Gopher Can Do It …". Time Magazine. 1944-04-10. Retrieved 2009-05-20.
  3. Becker GJ, Hewitson TD (March 2001). "Relaxin and renal fibrosis". Kidney International. 59 (3): 1184–5. doi:10.1046/j.1523-1755.2001.0590031184.x. PMID 11231378.
  4. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (February 2005). "Evolution of the relaxin-like peptide family". BMC Evolutionary Biology. 5: 14. doi:10.1186/1471-2148-5-14. PMC 551602. PMID 15707501.
  5. MacLennan AH (1991). "The role of the hormone relaxin in human reproduction and pelvic girdle relaxation". Scandinavian Journal of Rheumatology. Supplement. 88: 7–15. PMID 2011710.
  6. Hossain MA, Rosengren KJ, Samuel CS, Shabanpoor F, Chan LJ, Bathgate RA, Wade JD (October 2011). "The minimal active structure of human relaxin-2". The Journal of Biological Chemistry. 286 (43): 37555–65. doi:10.1074/jbc.M111.282194. PMC 3199501. PMID 21878627.
  7. Hayes ES (June 2004). "Biology of primate relaxin: a paracrine signal in early pregnancy?". Reproductive Biology and Endocrinology. 2 (36): 36. doi:10.1186/1477-7827-2-36. PMC 449733. PMID 15200675.
  8. Carp H, Torchinsky A, Fein A, Toder V (December 2001). "Hormones, cytokines and fetal anomalies in habitual abortion". Gynecological Endocrinology. 15 (6): 472–83. doi:10.1080/gye.15.6.472.483. PMID 11826772.
  9. Conrad KP (August 2011). "Maternal vasodilation in pregnancy: the emerging role of relaxin". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 301 (2): R267-75. doi:10.1152/ajpregu.00156.2011. PMC 3154715. PMID 21613576.
  10. Weiss G (February 1989). "Relaxin in the male". Biology of Reproduction. 40 (2): 197–200. doi:10.1095/biolreprod40.2.197. PMID 2497805. Archived from the original on 2008-11-22.
  11. Raleigh JM, Toldo S, Das A, Abbate A, Salloum FN (July 2016). "Relaxin' the Heart: A Novel Therapeutic Modality". Journal of Cardiovascular Pharmacology and Therapeutics. 21 (4): 353–62. doi:10.1177/1074248415617851. PMID 26589290.
  12. Feijóo-Bandín S, Aragón-Herrera A, Rodríguez-Penas D, Portolés M, Roselló-Lletí E, Rivera M, González-Juanatey JR, Lago F (2017). "Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives". Frontiers in Physiology. 8: 599. doi:10.3389/fphys.2017.00599. PMC 5563388. PMID 28868039.
  13. Mookerjee I, Solly NR, Royce SG, Tregear GW, Samuel CS, Tang ML (February 2006). "Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease". Endocrinology. 147 (2): 754–61. doi:10.1210/en.2005-1006. PMID 16254028.
  14. Arroyo JI, Hoffmann FG, Opazo JC (February 2012). "Gene duplication and positive selection explains unusual physiological roles of the relaxin gene in the European rabbit". Journal of Molecular Evolution. 74 (1–2): 52–60. doi:10.1007/s00239-012-9487-2. PMID 22354201.
  15. Klein C (July 2016). "The role of relaxin in mare reproductive physiology: A comparative review with other species". Theriogenology. 86 (1): 451–6. doi:10.1016/j.theriogenology.2016.04.061. PMID 27158127.
  16. Klein C (July 2016). "Early pregnancy in the mare: old concepts revisited". Domestic Animal Endocrinology. 56 Suppl: S212-7. doi:10.1016/j.domaniend.2016.03.006. PMID 27345319.
  17. Ousey JC (December 2006). "Hormone profiles and treatments in the late pregnant mare". The Veterinary Clinics of North America. Equine Practice. 22 (3): 727–47. doi:10.1016/j.cveq.2006.08.004. PMID 17129800.
  18. Pashen RL (July 1984). "Maternal and foetal endocrinology during late pregnancy and parturition in the mare". Equine Veterinary Journal. 16 (4): 233–8. doi:10.1111/j.2042-3306.1984.tb01918.x. PMID 6383806.
  19. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ (January 2002). "Activation of orphan receptors by the hormone relaxin". Science. 295 (5555): 671–4. doi:10.1126/science.1065654. PMID 11809971.
  20. Marshall SA, Senadheera SN, Parry LJ, Girling JE (March 2017). "The Role of Relaxin in Normal and Abnormal Uterine Function During the Menstrual Cycle and Early Pregnancy". Reproductive Sciences. 24 (3): 342–354. doi:10.1177/1933719116657189. PMID 27365367.
  21. Van Der Westhuizen ET, Summers RJ, Halls ML, Bathgate RA, Sexton PM (January 2007). "Relaxin receptors—new drug targets for multiple disease states". Current Drug Targets. 8 (1): 91–104. doi:10.2174/138945007779315650. PMID 17266534.
  22. Arroyo JI, Hoffmann FG, Opazo JC (March 2014). "Evolution of the relaxin/insulin-like gene family in anthropoid primates". Genome Biology and Evolution. 6 (3): 491–9. doi:10.1093/gbe/evu023. PMC 3971578. PMID 24493383.
  • Relaxin' at the US National Library of Medicine Medical Subject Headings (MeSH)
  • "Relaxin". Human Protein Reference Database. Johns Hopkins University and the Institute of Bioinformatics. Retrieved 2009-05-20.
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