Login Register Cart 0
Review Article

人重组松弛素 (Serelaxin) 作为抗纤维化剂：药理学、局限性的实际前景

卷 22, 期 3, 2022

发表于: 09 March, 2021

页: [196 - 208] 页: 13

弟呕挨: 10.2174/1566524021666210309113650

open access plus

摘要

松弛素（重组人松弛素 2 激素；RLX-2；serelaxin）作为一种新的治疗纤维化疾病的药物引起了人们的期望。大量的体外和体内研究提供了令人信服的证据，即松弛素促进结缔组织细胞外基质的重塑，通过抑制多种纤维化途径介导，特别是转化生长因子 (TGF)-β1（一种主要的促纤维化细胞因子）的下游信号传导，以及肌成纤维细胞（主要的纤维化生成细胞）的募集和激活。然而，所有在纤维化疾病患者中使用松弛素的临床试验都给出了不确定的结果。在这篇综述中，我们总结了纤维化的分子机制，重点介绍了松弛素可以有效靶向的分子机制。然后，我们对迄今为止使用松弛素作为抗纤维化药物进行的临床试验进行了严格的重新评估，以突出其优势和劣势的关键点，并确定松弛素或其治疗用途的一些未来机会。类似物，在我们认为值得研究的纤维化疾病和病理性瘢痕形成中。

关键词: 结缔组织、细胞外基质 (ECM)、纤维化、肌成纤维细胞、松弛素 (RLX)、RXFP1、sereleaxin、TGF-β

« Previous Next »
[1]
Hisaw F. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 1926; 3(8): 661-3.
[http://dx.doi.org/10.3181/00379727-23-3107]
[2]
Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev 2006; 58(1): 7-31.
[http://dx.doi.org/10.1124/pr.58.1.9] [PMID: 16507880]
[3]
Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Relaxin family peptides and their receptors. Physiol Rev 2013; 93(1): 405-80.
[http://dx.doi.org/10.1152/physrev.00001.2012] [PMID: 23303914]
[4]
Samuel CS, Lekgabe ED, Mookerjee I. The effects of relaxin on extracellular matrix remodeling in health and fibrotic disease. Adv Exp Med Biol 2007; 612: 88-103.
[http://dx.doi.org/10.1007/978-0-387-74672-2_7] [PMID: 18161483]
[5]
Hsu SY, Nakabayashi K, Nishi S, et al. Activation of orphan receptors by the hormone relaxin. Science 2002; 295(5555): 671-4.
[http://dx.doi.org/10.1126/science.1065654] [PMID: 11809971]
[6]
Unemori EN, Pickford LB, Salles AL, et al. Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest 1996; 98(12): 2739-45.
[http://dx.doi.org/10.1172/JCI119099] [PMID: 8981919]
[7]
Mookerjee I, Hewitson TD, Halls ML, et al. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J 2009; 23(4): 1219-29.
[http://dx.doi.org/10.1096/fj.08-120857] [PMID: 19073841]
[8]
Hewitson TD, Ho WY, Samuel CS. Antifibrotic properties of relaxin: in vivo mechanism of action in experimental renal tubulointerstitial fibrosis. Endocrinology 2010; 151(10): 4938-48.
[http://dx.doi.org/10.1210/en.2010-0286] [PMID: 20826562]
[9]
Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD, Samuel CS. Relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to up-regulate matrix metalloproteinases: the additional involvement of iNOS. PLoS One 2012; 7(8): e42714.
[http://dx.doi.org/10.1371/journal.pone.0042714] [PMID: 22936987]
[10]
Samuel CS, Zhao C, Bathgate RA, et al. The relaxin gene-knockout mouse: a model of progressive fibrosis. Ann N Y Acad Sci 2005; 1041: 173-81.
[http://dx.doi.org/10.1196/annals.1282.025] [PMID: 15956703]
[11]
Bennett RG. Relaxin and its role in the development and treatment of fibrosis. Transl Res 2009; 154(1): 1-6.
[http://dx.doi.org/10.1016/j.trsl.2009.03.007] [PMID: 19524867]
[12]
Samuel CS, Royce SG, Hewitson TD, Denton KM, Cooney TE, Bennett RG. Anti-fibrotic actions of relaxin. Br J Pharmacol 2017; 174(10): 962-76.
[http://dx.doi.org/10.1111/bph.13529] [PMID: 27250825]
[13]
Zeisberg M, Kalluri R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol 2013; 304(3): C216-25.
[http://dx.doi.org/10.1152/ajpcell.00328.2012] [PMID: 23255577]
[14]
Doljanski F. The sculpturing role of fibroblast-like cells in morphogenesis. Perspect Biol Med 2004; 47(3): 339-56.
[http://dx.doi.org/10.1353/pbm.2004.0048] [PMID: 15247501]
[15]
Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126(4): 677-89.
[http://dx.doi.org/10.1016/j.cell.2006.06.044] [PMID: 16923388]
[16]
Bani D, Nistri S. New insights into the morphogenic role of stromal cells and their relevance for regenerative medicine. lessons from the heart. J Cell Mol Med 2014; 18(3): 363-70.
[http://dx.doi.org/10.1111/jcmm.12247] [PMID: 24533677]
[17]
Pakshir P, Hinz B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol 2018; 68-69: 81-93.
[http://dx.doi.org/10.1016/j.matbio.2018.01.019] [PMID: 29408013]
[18]
Jun JI, Lau LF. Resolution of organ fibrosis. J Clin Invest 2018; 128(1): 97-107.
[http://dx.doi.org/10.1172/JCI93563] [PMID: 29293097]
[19]
Horowitz JC, Thannickal VJ. Mechanisms for the resolution of organ fibrosis. Physiology (Bethesda) 2019; 34(1): 43-55.
[http://dx.doi.org/10.1152/physiol.00033.2018] [PMID: 30540232]
[20]
Mack M, Yanagita M. Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int 2015; 87(2): 297-307.
[http://dx.doi.org/10.1038/ki.2014.287] [PMID: 25162398]
[21]
Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science 2017; 356(6342): 1026-30.
[http://dx.doi.org/10.1126/science.aam7928] [PMID: 28596335]
[22]
Mack M. Inflammation and fibrosis. Matrix Biol 2018; 68-69: 106-21.
[http://dx.doi.org/10.1016/j.matbio.2017.11.010] [PMID: 29196207]
[23]
Rosenbloom J, Macarak E, Piera-Velazquez S, Jimenez SA. Human fibrotic diseases: current challenges in fibrosis research. Methods Mol Biol 2017; 1627: 1-23.
[http://dx.doi.org/10.1007/978-1-4939-7113-8_1] [PMID: 28836191]
[24]
Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med 2019; 65: 2-15.
[http://dx.doi.org/10.1016/j.mam.2018.06.003] [PMID: 29958900]
[25]
Squecco R, Chellini F, Idrizaj E, et al. Platelet-rich plasma modulates gap junction functionality and connexin 43 and 26 expression during TGF-β1-induced fibroblast to myofibroblast transition: clues for counteracting fibrosis. Cells 2020; 9(5): 1199.
[http://dx.doi.org/10.3390/cells9051199] [PMID: 32408529]
[26]
Hinz B. Masters and servants of the force: the role of matrix adhesions in myofibroblast force perception and transmission. Eur J Cell Biol 2006; 85(3-4): 175-81.
[http://dx.doi.org/10.1016/j.ejcb.2005.09.004] [PMID: 16546559]
[27]
Hinz B, McCulloch CA, Coelho NM. Mechanical regulation of myofibroblast phenoconversion and collagen contraction. Exp Cell Res 2019; 379(1): 119-28.
[http://dx.doi.org/10.1016/j.yexcr.2019.03.027] [PMID: 30910400]
[28]
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119(6): 1420-8.
[http://dx.doi.org/10.1172/JCI39104] [PMID: 19487818]
[29]
Rock JR, Barkauskas CE, Cronce MJ, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci USA 2011; 108(52): E1475-83.
[http://dx.doi.org/10.1073/pnas.1117988108] [PMID: 22123957]
[30]
Brenner DA, Kisseleva T, Scholten D, et al. Origin of myofibroblasts in liver fibrosis. Fibrogenesis Tissue Repair 2012; 5(Suppl. 1): S17.
[http://dx.doi.org/10.1186/1755-1536-5-S1-S17] [PMID: 23259769]
[31]
LeBleu VS, Taduri G, O’Connell J, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013; 19(8): 1047-53.
[http://dx.doi.org/10.1038/nm.3218] [PMID: 23817022]
[32]
Pérez L, Muñoz-Durango N, Riedel CA, et al. Endothelial-to-mesenchymal transition: Cytokine-mediated pathways that determine endothelial fibrosis under inflammatory conditions. Cytokine Growth Factor Rev 2017; 33: 41-54.
[http://dx.doi.org/10.1016/j.cytogfr.2016.09.002] [PMID: 27692608]
[33]
Van De Water L, Varney S, Tomasek JJ. Mechanoregulation of the myofibroblast in wound contraction, scarring, and fibrosis: opportunities for new therapeutic intervention. Adv Wound Care (New Rochelle) 2013; 2(4): 122-41.
[http://dx.doi.org/10.1089/wound.2012.0393] [PMID: 24527336]
[34]
Pakshir P, Alizadehgiashi M, Wong B, Coelho NM, Chen X, Gong Z, et al. Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix. Nat Commun 2019; 10(1): 1850. Authors’ correction 2019; 10(1): 2286.
[http://dx.doi.org/10.1038/s41467-019-09709-6] [PMID: 31015429] [http://dx.doi.org/10.1038/s41467-019-10344-4] [PMID: 31110254]
[35]
Borges FT, Melo SA, Özdemir BC, et al. TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol 2013; 24(3): 385-92.
[http://dx.doi.org/10.1681/ASN.2012101031] [PMID: 23274427]
[36]
Caja L, Dituri F, Mancarella S, et al. TGF-β and the tissue microenvironment: relevance in fibrosis and cancer. Int J Mol Sci 2018; 19(5): 1294.
[http://dx.doi.org/10.3390/ijms19051294] [PMID: 29701666]
[37]
He W, Dai C. Key Fibrogenic Signaling. Curr Pathobiol Rep 2015; 3(2): 183-92.
[http://dx.doi.org/10.1007/s40139-015-0077-z] [PMID: 25973345]
[38]
Szeto SG, Narimatsu M, Lu M, et al. YAP/TAZ are mechanoregulators of TGF-β-Smad signaling and renal fibrogenesis. J Am Soc Nephrol 2016; 27(10): 3117-28.
[http://dx.doi.org/10.1681/ASN.2015050499] [PMID: 26961347]
[39]
Noguchi S, Saito A, Nagase T. YAP/TAZ signaling as a molecular link between fibrosis and cancer. Int J Mol Sci 2018; 19(11): 3674.
[http://dx.doi.org/10.3390/ijms19113674] [PMID: 30463366]
[40]
Kim CL, Choi SH, Mo JS. Role of the Hippo pathway in fibrosis and cancer. Cells 2019; 8(5): 468.
[http://dx.doi.org/10.3390/cells8050468] [PMID: 31100975]
[41]
Dey A, Varelas X, Guan KL. Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat Rev Drug Discov 2020; 19(7): 480-94.
[http://dx.doi.org/10.1038/s41573-020-0070-z] [PMID: 32555376]
[42]
Tsou PS, Haak AJ, Khanna D, Neubig RR. Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription. Am J Physiol Cell Physiol 2014; 307(1): C2-C13.
[http://dx.doi.org/10.1152/ajpcell.00060.2014] [PMID: 24740541]
[43]
Cheon SS, Wei Q, Gurung A, et al. Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing. FASEB J 2006; 20(6): 692-701.
[http://dx.doi.org/10.1096/fj.05-4759com] [PMID: 16581977]
[44]
Sato M. Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids. Acta Derm Venereol 2006; 86(4): 300-7.
[http://dx.doi.org/10.2340/00015555-0101] [PMID: 16874413]
[45]
Carre AL, James AW, MacLeod L, et al. Interaction of wingless protein (Wnt), transforming growth factor-beta1, and hyaluronan production in fetal and postnatal fibroblasts. Plast Reconstr Surg 2010; 125(1): 74-88.
[http://dx.doi.org/10.1097/PRS.0b013e3181c495d1] [PMID: 20048602]
[46]
AlQudah M, Hale TM, Czubryt MP. Targeting the renin-angiotensin-aldosterone system in fibrosis. Matrix Biol 2020; S0945-053X(20): 30050-0.
[http://dx.doi.org/10.1016/j.matbio.2020.04.005] [PMID: 32422329]
[47]
Shimojo N, Hashizume R, Kanayama K, et al. Tenascin-C may accelerate cardiac fibrosis by activating macrophages via the integrin αVβ3/nuclear factor-κB/interleukin-6 axis. Hypertension 2015; 66(4): 757-66.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06004] [PMID: 26238448]
[48]
Flevaris P, Khan SS, Eren M, et al. Plasminogen activator inhibitor type I controls cardiomyocyte transforming growth factor-β and cardiac fibrosis. Circulation 2017; 136(7): 664-79.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028145] [PMID: 28588076]
[49]
Chow BS, Kocan M, Bosnyak S, et al. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. Kidney Int 2014; 86(1): 75-85.
[http://dx.doi.org/10.1038/ki.2013.518] [PMID: 24429402]
[50]
Sassoli C, Chellini F, Squecco R, et al. Low intensity 635 nm diode laser irradiation inhibits fibroblast-myofibroblast transition reducing TRPC1 channel expression/activity: New perspectives for tissue fibrosis treatment. Lasers Surg Med 2016; 48(3): 318-32.
[http://dx.doi.org/10.1002/lsm.22441] [PMID: 26660509]
[51]
Sassoli C, Chellini F, Pini A, et al. Relaxin prevents cardiac fibroblast-myofibroblast transition via notch-1-mediated inhibition of TGF-β/Smad3 signaling. PLoS One 2013; 8(5): e63896.
[http://dx.doi.org/10.1371/journal.pone.0063896] [PMID: 23704950]
[52]
Halls ML, van der Westhuizen ET, Bathgate RA, Summers RJ. Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol 2007; 150(6): 677-91.
[http://dx.doi.org/10.1038/sj.bjp.0707140] [PMID: 17293890]
[53]
Valkovic AL, Bathgate RA, Samuel CS, Kocan M. Understanding relaxin signalling at the cellular level. Mol Cell Endocrinol 2019; 487: 24-33.
[http://dx.doi.org/10.1016/j.mce.2018.12.017] [PMID: 30592984]
[54]
Ng HH, Shen M, Samuel CS, Schlossmann J, Bennett RG. Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways. Mol Cell Endocrinol 2019; 487: 59-65.
[http://dx.doi.org/10.1016/j.mce.2019.01.015] [PMID: 30660699]
[55]
Palejwala S, Stein D, Wojtczuk A, Weiss G, Goldsmith LT. Demonstration of a relaxin receptor and relaxin-stimulated tyrosine phosphorylation in human lower uterine segment fibroblasts. Endocrinology 1998; 139(3): 1208-12.
[http://dx.doi.org/10.1210/endo.139.3.5772] [PMID: 9492055]
[56]
Huang X, Gai Y, Yang N, et al. Relaxin regulates myofibroblast contractility and protects against lung fibrosis. Am J Pathol 2011; 179(6): 2751-65.
[http://dx.doi.org/10.1016/j.ajpath.2011.08.018] [PMID: 21983071]
[57]
Bartsch O, Bartlick B, Ivell R. Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod 2001; 7(9): 799-809.
[http://dx.doi.org/10.1093/molehr/7.9.799] [PMID: 11517286]
[58]
Nguyen BT, Yang L, Sanborn BM, Dessauer CW. Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3′,5′-monophosphate by relaxin. Mol Endocrinol 2003; 17(6): 1075-84.
[http://dx.doi.org/10.1210/me.2002-0284] [PMID: 12595573]
[59]
Bartscha O, Ivell R. Relaxin and phosphodiesterases collaborate during decidualization. Ann N Y Acad Sci 2004; 1030: 479-92.
[http://dx.doi.org/10.1196/annals.1329.060] [PMID: 15659833]
[60]
McGuane JT, Debrah JE, Sautina L, et al. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology 2011; 152(7): 2786-96.
[http://dx.doi.org/10.1210/en.2010-1126] [PMID: 21558316]
[61]
Ahmad N, Wang W, Nair R, Kapila S. Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-ζ pathways. Mol Cell Endocrinol 2012; 363(1-2): 46-61.
[http://dx.doi.org/10.1016/j.mce.2012.07.006] [PMID: 22835547]
[62]
Boccalini G, Sassoli C, Bani D, Nistri S. Relaxin induces up-regulation of ADAM10 metalloprotease in RXFP1-expressing cells by PI3K/AKT signaling. Mol Cell Endocrinol 2018; 472: 80-6.
[http://dx.doi.org/10.1016/j.mce.2017.11.021] [PMID: 29180109]
[63]
Zhang Q, Liu SH, Erikson M, Lewis M, Unemori E. Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem 2002; 85(3): 536-44.
[http://dx.doi.org/10.1002/jcb.10150] [PMID: 11967993]
[64]
Dschietzig T, Bartsch C, Richter C, Laule M, Baumann G, Stangl K. Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 2003; 92(1): 32-40.
[http://dx.doi.org/10.1161/01.RES.0000051884.27117.7E] [PMID: 12522118]
[65]
Masini E, Bani D, Bigazzi M, Mannaioni PF, Bani-Sacchi T. Effects of relaxin on mast cells. In vitro and in vivo studies in rats and guinea pigs. J Clin Invest 1994; 94(5): 1974-80.
[http://dx.doi.org/10.1172/JCI117549] [PMID: 7525651]
[66]
Bigazzi M, Del Mese A, Petrucci F, Casali R, Novelli GP. The local administration of relaxin induces changes in the microcirculation of the rat mesocaecum. Acta Endocrinol (Copenh) 1986; 112(2): 296-9.
[http://dx.doi.org/10.1530/acta.0.1120296] [PMID: 3739555]
[67]
Bani G, Bani Sacchi T, Bigazzi M, Bianchi S. Effects of relaxin on the microvasculature of mouse mammary gland. Histol Histopathol 1988; 3(4): 337-43.
[PMID: 2980242]
[68]
Bani-Sacchi T, Bigazzi M, Bani D, Mannaioni PF, Masini E. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol 1995; 116(1): 1589-94.
[http://dx.doi.org/10.1111/j.1476-5381.1995.tb16377.x] [PMID: 8564223]
[69]
Bani D, Failli P, Bello MG, et al. Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension 1998; 31(6): 1240-7.
[http://dx.doi.org/10.1161/01.HYP.31.6.1240] [PMID: 9622136]
[70]
Bani D. Recombinant human H2 relaxin (serelaxin) as a cardiovascular drug: aiming at the right target. Drug Discov Today 2020; 25(7): 1239-44.
[http://dx.doi.org/10.1016/j.drudis.2020.04.014] [PMID: 32360533]
[71]
Fallowfield JA, Hayden AL, Snowdon VK, et al. Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology 2014; 59(4): 1492-504.
[http://dx.doi.org/10.1002/hep.26627] [PMID: 23873655]
[72]
Wang C, Kemp-Harper BK, Kocan M, Ang SY, Hewitson TD, Samuel CS. The anti-fibrotic actions of relaxin are mediated through a NO-sGC-cGMP-dependent pathway in renal myofibroblasts in vitro and enhanced by the NO donor, diethylamine NONOate. Front Pharmacol 2016; 7: 91.
[http://dx.doi.org/10.3389/fphar.2016.00091] [PMID: 27065874]
[73]
Nistri S, Bani D. Relaxin receptors and nitric oxide synthases: search for the missing link. Reprod Biol Endocrinol 2003; 1: 5.
[http://dx.doi.org/10.1186/1477-7827-1-5] [PMID: 12646076]
[74]
Alexiou K, Wilbring M, Matschke K, Dschietzig T. Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1. PLoS One 2013; 8(9): e75592.
[http://dx.doi.org/10.1371/journal.pone.0075592] [PMID: 24098703]
[75]
Conrad KP, Novak J. Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integr Comp Physiol 2004; 287(2): R250-61.
[http://dx.doi.org/10.1152/ajpregu.00672.2003] [PMID: 15271674]
[76]
Bani D. Relaxin as a natural agent for vascular health. Vasc Health Risk Manag 2008; 4(3): 515-24.
[http://dx.doi.org/10.2147/VHRM.S2177] [PMID: 18827902]
[77]
Wetzl V, Schinner E, Kees F, Hofmann F, Faerber L, Schlossmann J. Involvement of cyclic guanosine monophosphate-dependent protein kinase I in renal antifibrotic effects of serelaxin. Front Pharmacol 2016; 7: 195.
[http://dx.doi.org/10.3389/fphar.2016.00195] [PMID: 27462268]
[78]
Unemori EN, Lewis M, Constant J, et al. Relaxin induces vascular endothelial growth factor expression and angiogenesis selectively at wound sites. Wound Repair Regen 2000; 8(5): 361-70.
[http://dx.doi.org/10.1111/j.1524-475X.2000.00361.x] [PMID: 11186125]
[79]
Palejwala S, Tseng L, Wojtczuk A, Weiss G, Goldsmith LT. Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells. Biol Reprod 2002; 66(6): 1743-8.
[http://dx.doi.org/10.1095/biolreprod66.6.1743] [PMID: 12021056]
[80]
Formigli L, Perna AM, Meacci E, et al. Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling. J Cell Mol Med 2007; 11(5): 1087-100.
[http://dx.doi.org/10.1111/j.1582-4934.2007.00111.x] [PMID: 17979884]
[81]
Sarwar M, Samuel CS, Bathgate RA, Stewart DR, Summers RJ. Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration-response curves reflect differential coupling to G proteins. Br J Pharmacol 2015; 172(4): 1005-19.
[http://dx.doi.org/10.1111/bph.12964] [PMID: 25297987]
[82]
Chellini F, Tani A, Vallone L, et al. Platelet-rich plasma prevents in vitro transforming growth factor-β1-induced fibroblast to myofibroblast transition: involvement of vascular endothelial growth factor (VEGF)-A/VEGF receptor-1-mediated signaling†. Cells 2018; 7(9): 142.
[http://dx.doi.org/10.3390/cells7090142] [PMID: 30235859]
[83]
Frati A, Ricci B, Pierucci F, Nistri S, Bani D, Meacci E. Role of sphingosine kinase/S1P axis in ECM remodeling of cardiac cells elicited by relaxin. Mol Endocrinol 2015; 29(1): 53-67.
[http://dx.doi.org/10.1210/me.2014-1201] [PMID: 25415609]
[84]
Zhou X, Chen X, Cai JJ, et al. Relaxin inhibits cardiac fibrosis and endothelial-mesenchymal transition via the Notch pathway. Drug Des Devel Ther 2015; 9: 4599-611.
[http://dx.doi.org/10.2147/DDDT.S85399] [PMID: 26316699]
[85]
Pini A, Shemesh R, Samuel CS, et al. Prevention of bleomycin-induced pulmonary fibrosis by a novel antifibrotic peptide with relaxin-like activity. J Pharmacol Exp Ther 2010; 335(3): 589-99.
[http://dx.doi.org/10.1124/jpet.110.170977] [PMID: 20826567]
[86]
Hossain MA, Kocan M, Yao ST, et al. A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1. Chem Sci (Camb) 2016; 7(6): 3805-19.
[http://dx.doi.org/10.1039/C5SC04754D] [PMID: 30155023]
[87]
Agoulnik AI, Agoulnik IU, Hu X, Marugan J. Synthetic non-peptide low molecular weight agonists of the relaxin receptor 1. Br J Pharmacol 2017; 174(10): 977-89.
[http://dx.doi.org/10.1111/bph.13656] [PMID: 27771940]
[88]
Praveen P, Kocan M, Valkovic A, Bathgate R, Hossain MA. Single chain peptide agonists of relaxin receptors. Mol Cell Endocrinol 2019; 487: 34-9.
[http://dx.doi.org/10.1016/j.mce.2019.01.008] [PMID: 30641102]
[89]
Bani D, Yue SK, Bigazzi M. Clinical profile of relaxin, a possible new drug for human use. Curr Drug Saf 2009; 4(3): 238-49.
[http://dx.doi.org/10.2174/157488609789006967] [PMID: 19534649]
[90]
Casten GG, Boucek RJ. Use of relaxin in the treatment of scleroderma. J Am Med Assoc 1958; 166(4): 319-24.
[http://dx.doi.org/10.1001/jama.1958.02990040005002] [PMID: 13491339]
[91]
Reynolds H, Livingwood CS. Use of relaxin in management of ulceration and gangrene due to collagen disease. AMA Arch Derm 1959; 80(4): 407-9.
[http://dx.doi.org/10.1001/archderm.1959.01560220017003] [PMID: 13636425]
[92]
Rivelis AL, Traeger C, Rogoff B. The use of relaxin in progressive systemic sclerosis and other connective tissue diseases. A clinical study. Arch Interam Rheumatol 1965; 8: 19-31.
[PMID: 14316749]
[93]
Seibold JR, Korn JH, Simms R, et al. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 132(11): 871-9.
[http://dx.doi.org/10.7326/0003-4819-132-11-200006060-00004] [PMID: 10836913]
[94]
Kern A, Bryant-Greenwood GD. Characterization of relaxin receptor (RXFP1) desensitization and internalization in primary human decidual cells and RXFP1-transfected HEK293 cells. Endocrinology 2009; 150(5): 2419-28.
[http://dx.doi.org/10.1210/en.2008-1385] [PMID: 19116340]
[95]
Giordano N, Volpi N, Franci D, et al. Expression of RXFP1 in skin of scleroderma patients and control subjects. Scand J Rheumatol 2012; 41(5): 391-5.
[http://dx.doi.org/10.3109/03009742.2012.669496] [PMID: 23043266]
[96]
Corallo C, Pinto AM, Renieri A, Cheleschi S, Fioravanti A, Cutolo M, et al. Altered expression of RXFP1 receptor contributes to the inefficacy of relaxin-based anti-fibrotic treatments in systemic sclerosis. Clin Exp Rheumatol 2019; 37((Suppl )119(4): 69-75.
[PMID: 31365333]
[97]
Kurmani S, Squire I. Acute heart failure: Definition, classification and epidemiology. Curr Heart Fail Rep 2017; 14(5): 385-92.
[http://dx.doi.org/10.1007/s11897-017-0351-y] [PMID: 28785969]
[98]
Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009; 373(9673): 1429-39.
[http://dx.doi.org/10.1016/S0140-6736(09)60622-X] [PMID: 19329178]
[99]
Teerlink JR, Cotter G, Davison BA, et al. RELAXin in Acute Heart Failure (RELAX-AHF) Investigators. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013; 381(9860): 29-39.
[http://dx.doi.org/10.1016/S0140-6736(12)61855-8] [PMID: 23141816]
[100]
Teerlink JR, Davison BA, Cotter G, et al. Effects of serelaxin in patients admitted for acute heart failure: a meta-analysis. Eur J Heart Fail 2020; 22(2): 315-29.
[http://dx.doi.org/10.1002/ejhf.1692] [PMID: 31886953]
[101]
Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev 2004; 25(2): 205-34.
[http://dx.doi.org/10.1210/er.2003-0013] [PMID: 15082520]
[102]
MacLennan AH, Green RC, Grant P, Nicolson R. Ripening of the human cervix and induction of labor with intracervical purified porcine relaxin. Obstet Gynecol 1986; 68(5): 598-601.
[PMID: 3531936]
[103]
Bell RJ, Permezel M, MacLennan A, Hughes C, Healy D, Brennecke S. A randomized, double-blind, placebo-controlled trial of the safety of vaginal recombinant human relaxin for cervical ripening. Obstet Gynecol 1993; 82(3): 328-33.
[PMID: 8355929]
[104]
Brennand JE, Calder AA, Leitch CR, Greer IA, Chou MM, MacKenzie IZ. Recombinant human relaxin as a cervical ripening agent. Br J Obstet Gynaecol 1997; 104(7): 775-80.
[http://dx.doi.org/10.1111/j.1471-0528.1997.tb12019.x] [PMID: 9236640]
[105]
Kelly AJ, Kavanagh J, Thomas J. Relaxin for cervical ripening and induction of labour. Cochrane Database Syst Rev 2001; 2(2): CD003103.
[http://dx.doi.org/10.1002/14651858.CD003103] [PMID: 11406079]
[106]
Martins RC, Pintalhão M, Leite-Moreira A, Castro-Chaves P. Relaxin and the cardiovascular system: from basic science to clinical practice. Curr Mol Med 2020; 20(3): 167-84.
[http://dx.doi.org/10.2174/1566524019666191023121607] [PMID: 31642776]
[107]
Chow BSM, Kocan M, Shen M, et al. AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts: impact on the therapeutic targeting of renal and cardiac fibrosis. J Am Soc Nephrol 2019; 30(11): 2191-207.
[http://dx.doi.org/10.1681/ASN.2019060597] [PMID: 31511361]
[108]
Chen SA, Perlman AJ, Spanski N, et al. The pharmacokinetics of recombinant human relaxin in nonpregnant women after intravenous, intravaginal, and intracervical administration. Pharm Res 1993; 10(6): 834-8.
[http://dx.doi.org/10.1023/A:1018901009062] [PMID: 8257492]
[109]
Bani D, Pini A, Yue SK. Relaxin, insulin and diabetes: an intriguing connection. Curr Diabetes Rev 2012; 8(5): 329-35.
[http://dx.doi.org/10.2174/157339912802083487] [PMID: 22698078]
[110]
Ma J, Niu M, Yang W, Zang L, Xi Y. Role of relaxin-2 in human primary osteosarcoma. Cancer Cell Int 2013; 13(1): 59.
[http://dx.doi.org/10.1186/1475-2867-13-59] [PMID: 23758748]
[111]
Kibblewhite D, Larrabee WF Jr, Sutton D. The effect of relaxin on tissue expansion. Arch Otolaryngol Head Neck Surg 1992; 118(2): 153-6.
[http://dx.doi.org/10.1001/archotol.1992.01880020047014] [PMID: 1540345]
[112]
Gharaee-Kermani M, Hu B, Phan SH, Gyetko MR. Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblast. Curr Med Chem 2009; 16(11): 1400-17.
[http://dx.doi.org/10.2174/092986709787846497] [PMID: 19355895]
[113]
Ferlin A, De Toni L, Sandri M, Foresta C. Relaxin and insulin-like peptide 3 in the musculoskeletal system: from bench to bedside. Br J Pharmacol 2017; 174(10): 1015-24.
[http://dx.doi.org/10.1111/bph.13490] [PMID: 27059798]
[114]
Blessing WA, Okajima SM, Cubria MB, et al. Intraarticular injection of relaxin-2 alleviates shoulder arthrofibrosis. Proc Natl Acad Sci USA 2019; 116(25): 12183-92.
[http://dx.doi.org/10.1073/pnas.1900355116] [PMID: 31160441]
[115]
Xiao J, Huang Z, Chen CZ, et al. Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1. Nat Commun 2013; 4: 1953.
[http://dx.doi.org/10.1038/ncomms2953] [PMID: 23764525]

Rights & Permissions Print Cite
Article Metrics
43
1
© 2024 Bentham Science Publishers | Privacy Policy