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Relaxin Signaling Pathway


Figure 1. Relaxin signaling pathway

Relaxin overview

The relaxin signaling pathway refers to all proteins involved in the pathway of relaxin signaling pathway and related regulatory factors. Relaxin is a peptide hormone that relaxes the birth canal before delivery. Mainly produced in the corpus luteum of the ovary during mammalian pregnancy, it relaxes the pelvic ligament, loosens the pubic symphysis, and dilates the cervix and vagina. These are beneficial to the fetus output during the delivery of livestock. Relaxin is a peptide hormone discovered by Frederick Hisaw in 1926 during the study of changes in the pelvic tract during pregnancy. It is produced mainly in the body by the ovary and the placenta of pregnancy and the prostate of males. Because it has the function of relaxing the uterine smooth muscle, softening the cervix, relaxing pelvic ligament, etc., it is called relaxin. Relaxin in the blood circulation of humans and mammals has many biological functions. Early studies on relaxin mainly focused on its role in the reproductive system. As the research progressed, the researchers found relaxin in the heart, liver, lung, and kidney. It is expressed on the skin and can be widely used in circulation, urinary, respiratory, nervous, and reproductive systems and organs, and is closely related to the occurrence of various diseases. Early research on relaxin focused on the role of the reproductive system, which has been found to have effects on the cardiovascular, urinary, respiratory, and digestive systems. The effects of several aspects are summarized as follows: (1) Reproductive system: It can regulate the uterus and cervical remodeling and growth during pregnancy, inhibit the contraction of uterine muscle during pregnancy to promote pregnancy, and promote endometrial thickening and endometrial angiogenesis; pelvic connective tissue and softened birth canal are used for childbirth. (2) Cardiovascular system: Lower blood pressure and vascular resistance. a. Increase cardiac output and heart rate. b. Reduce ischemia and reperfusion injury. c. Anti-myocardial fibrosis improves ventricular hypertrophy. (3) Urinary system: Increase glomerular filtration rate and renal blood flow. (4) Others: such as anti-lung and liver fibrosis.

Relaxin family

Relaxin has a molecular weight of 6 kD and consists of two peptide chains each containing 22 and 33 amino acid residues, with a disulfide bond in the chain. The median region of the relaxin B chain is the receptor binding region and contains two arginine residues, which are highly conserved among species. Although the A chain does not participate in receptor binding, it is still necessary, and the formation of the indole loop is the decisive structure of the relaxin conformation. The RLX sequence varies by more than 50% between different species, but animal experiments have found that the biological activities of different species of RLX are similar. There are three RLX genes in humans and higher animals, which express H1, H2 and H3 relaxin, respectively. H2RLX mainly exists in the circulation and acts on target organs. Rodents have two RLX genes, RLX-1 (equivalent to H2) and RLX-3 (equivalent to H3). RLX can be synthesized and secreted by various tissue cells in the body, and the corpus luteum and prostate are the main sites of RLX production. Non-reproductive systems, such as the brain, gastrointestinal tract, and atria, ventricles, also have RLX, relaxin precursors, or relaxin-like actives. RLX acts through receptors, and its receptors are mainly LGR7 and LGR8, which contain 757 and 737 amino acid residues. Both of them contain the same N-terminal extracellular domain and their major structures include 10 leucine repeats (LRR) and low-density lipoprotein A (LDLa) sequences. H2RLX and LGR7 and LGR8 can be combined, but H3RLX can only be applied to LGR7. LRR and H2RLX have high affinity, and the LDLa sequence does not affect the binding of RLX to the receptor but can affect the cell signal transduction after binding. In addition to the RLX receptor in the reproductive system, the central nervous system and heart are also densely distributed with high-affinity RLX receptors, but only high-affinity LGR7 receptors are found in the atria and ventricles, suggesting a cardiovascular effect of RLX.

Relaxin signaling pathway

  1. Relaxin signaling pathway cascade
  2. The relaxin signaling pathway is widely present in the body. We use the cardiovascular effect as an example to describe the way in which the relaxin signaling pathway works: the distribution and function of relaxin and its receptor RXFP1 are found in the cardiovascular system with an important role, such as dilating blood vessels, reducing ischemia-reperfusion injury and anti-myocardial fibrosis, and improving ventricular hypertrophy and anti-inflammatory effects. Many studies have shown that relaxin can dilate blood vessels and found that this vasodilator mechanism is related to its ability to increase endothelial nitric oxide (NO) production. Relaxin's dilated blood vessels are weaker than substance P, stronger than an atrial natriuretic peptide, and like epoprostenol, but this relaxation effect disappears after removal of the endothelium, suggesting that relaxin is a vasodilator effect through the endothelium. Dan et al (2005) found that acute injection of relaxin increased cardiac output and vascular compliance and reduced vascular resistance in an angiotensin II-induced hypertensive rat model. But this did not change the mean arterial pressure. Acute injection of relaxin in spontaneously hypertensive rats and normotensive rats did not affect cardiac output, vascular resistance, arterial compliance, or mean arterial pressure. However, chronic injection of relaxin increases cardiac output and vascular compliance, reduces vascular resistance but does not alter mean arterial pressure. Early studies have found that relaxin can increase heart rate and myocardial contractility in a dose-dependent manner. It is found that in isolated rat brains, the addition of relaxin to the reperfusion can increase the heart rate in a dose-dependent manner but does not affect the contractile force and reperfusion pressure. Relaxin refilling can cause an increase in the atrial natriuretic peptide (ANP), but the addition of a protein kinase C inhibitor can inhibit the effects of relaxin on ANP increase and heart rate increase. In addition, cAMP-dependent protein kinase inhibitors also inhibit this effect. Calmodulin-dependent protein kinase inhibitors reduce the positive chronotropic effects of relaxin but do not affect the secretion of ANP. It is suggested that relaxin regulates ANP secretion by activating protein kinase C and cAMP-dependent protein kinase pathways. Kompa et al (2002) showed a positive inotropic effect in the left atrium after relaxin treatment in a rat model of heart failure after acute myocardial infarction, but compared with the sham-operated group, the positive relaxin in the heart failure group after myocardial infarction muscle strength was reduced, and pertussis toxin (G protein receptor inhibitor) dd not affect the positive inotropic effect of relaxin on the left atrium of myocardial infarction. The sham-operated group and the heart failure group after myocardial infarction showed positive chronotropic effects after treatment with right atrial relaxin. This positive variability had no difference between the two groups and was not affected by pertussis toxin. In addition, the expression of RXFP1 in the atria and ventricles of myocardial infarction rats was found to be down-regulated compared with the sham-operated group. The study found that relaxin, a donor, and recipient of cardiac heart atrial myocytes, can increase contractility of donor and recipient cardiac atrial myocytes, possibly through protein kinase A and transient potassium efflux. The expression of RXFP1 in atrial myocytes was down-regulated in patients with heart failure. At the same time, relaxin can also reduce myocardial ischemia-reperfusion injury. Relaxin can improve myocardial ischemia-reperfusion injury, which is characterized by reducing myocardial necrosis markers, promoting NO production in coronary arteries and increasing coronary blood flow. In the rat model, relaxin was pre-administered to reduce the release of histamine and lactate dehydrogenase caused by ischemia-reperfusion and to increase coronary blood flow. The study found that the left anterior descending coronary artery of the guinea pig heart was induced to remove the ligation after ischemia. During reperfusion, the addition of relaxin to the perfusate increased coronary blood flow, promoted NO production, and reduced malondialdehyde (MDA) production. With calcium overload and inhibition of mast cell granule exocytosis and histamine release, it is found that this effect can be inhibited by NO synthase inhibitors, so it is believed that the protective effect of this relaxin on ischemia-reperfusion may be mediated by NO. The rat left heart anterior descending artery was ligated for 30 minutes and then reperfused for 60 minutes. Compared with the control group, the area of myocardial ischemia-reperfusion injury was reduced, and the incidence of ventricular arrhythmia was decreased in the 30-minute pre-ischemic pre-intravenous relaxin group. And mortality was reduced, myocardial neutrophil count, MDA production, and mast cell histamine release were reduced, and cellular calcium overload was reduced.

  3. Pathway regulation
  4. Shpakovet al. found that LGR7, which activates relaxin and activates the myocardium, exerts an interaction between the receptor and the GS protein through the interaction of the third intracellular loop of the C-terminus of the receptor with the C-terminal α-subunit of the GS protein. Halls et al. concluded that relaxin LGR7 functions not only with cAMP-protein kinase A (PKA) but also with the p38/JNK pathway in mitogen-activated protein kinases (MAPKs). The effect of relaxin on other cells outside the heart may be mainly through the G-protein-cAMP pathway; however, studies on rat cardiac fibroblasts have found that relaxin only causes transient minor changes in cAMP, which is resistant to cardiovascular fibrosis. The effect may not be through the cAMP pathway. In the study of uterine fibroblasts, inhibition of c-Ra f protein expression by antisense oligonucleotides abolished the inhibitory effect of relaxin on tissue inhibitor of metalloproteinases (TIMP), suggesting that the anti-fibrosis effect of relaxin is involved in c-Raf enzyme. Relaxin can also exert an anti-fibrotic effect indirectly by affecting other active factors. Relaxin inhibits the fibrosis of the kidney by inhibiting the TGFβ signaling pathway. Relaxin acts on human umbilical vein endothelial cells and epithelial cells to up-regulate the expression of endothelin ETB receptor, which antagonizes the pro-fibrotic effect of endothelin-1. Relaxin up-regulation of ETB receptor expression is mediated through activation of the ERK1/2 pathway and NF-κB pathway in MAPKs. Relaxin stimulates cardiac ANP secretion through activation of the protein kinase C (PKC) and cAMP-PKA pathways.

  5. Relationship with disease
  6. Cardiovascular fibrosis

    RLX is an endogenous anti-fibrotic defense system with multiple anti-fibrotic effects. It is a new target molecule for the prevention and treatment of myocardial fibrosis and has exciting potential clinical application prospects. The physiology, pathophysiology and pharmacological significance of relaxin deserve further study to facilitate its transformation into clinical applications.

    Coronary heart disease

    The latest research shows that by detecting the level of relaxin in the blood, it can help diagnose and prognose cardiovascular diseases. However, the level of serum relaxin in patients with coronary heart disease, and the possible relationship between relaxin and coronary heart disease have not been reported at home and abroad. Therefore, this study mainly explores the level of relaxin in patients with coronary heart disease to explore the significance of relaxin in assessing the condition of coronary heart disease and prognosis.

References:

  1. Kania A, Lewandowski M H, Błasiak A. Relaxin-3 and relaxin family peptide receptors--from structure to functions of a newly discovered mammalian brain system. Postepy Higieny I Medycyny Doswiadczalnej. 2014, 68(242):851.
  2. Bathgate R A, Halls M L, Et V D W, et al. Relaxin family peptides and their receptors. Physiological Reviews. 2013, 93(1):405-80.
  3. Bergfelt D R, Peter A T, Beg M A. Relaxin: a hormonal aid to diagnose pregnancy status in wild mammalian species. Theriogenology. 2014, 82(9):1187-1198.
  4. Kikkawa Y, Matsuo S, Kurogi R, et al. Upregulation of Relaxin after Experimental Subarachnoid Hemorrhage in Rabbits. Biomed Res Int. 2014, 2014(3):836397.
  5. Wang X Y, Guo Y Q, Zhang W J, et al. The electrostatic interactions of relaxin-3 with receptor RXFP4 and the influence of its B-chain C-terminal conformation. Febs Journal. 2014, 281(13):2927-2936.

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