Cardiovascular diseases (CVDs) are a group of disorders affecting the heart and blood vessels and a leading cause of death worldwide. Thus, there is a need to identify new cardiokines that may protect the heart from damage as reported in GBD 2017 Causes of Death Collaborators (2018) (The Lancet 392:1736-1788). Follistatin-like 1 (FSTL1) is a cardiokine that is highly expressed in the heart and released to the serum after cardiac injury where it is associated with CVD and predicts poor outcome. The action of FSTL1 likely depends not only on the tissue source but also post-translation modifications that are target tissue- and cell-specific. Animal studies examining the effect of FSTL1 in various models of heart disease have exploded over the past 15 years and primarily report a protective effect spanning from inhibiting inflammation via transforming growth factor, preventing remodeling and fibrosis to promoting angiogenesis and hypertrophy. A better understanding of FSTL1 and its homologs is needed to determine whether this protein could be a useful novel biomarker to predict poor outcome and death and whether it has therapeutic potential. The aim of this review is to provide a comprehensive description of the literature for this family of proteins in order to better understand their role in normal physiology and CVD.

Department of Cardiovascular Medicine Mayo Clinic 4500 San Pablo Road Jacksonville FL 32224 USA

Department of Pathological Physiology Faculty of Medicine Masaryk University Kamenice 5 Brno 625 00 Czech Republic

Research Centre for Toxic Compounds in the Environment Faculty of Science Masaryk University Kamenice 5 Brno 625 00 Czech Republic

Zobrazit více v PubMed

Oshima Y, Ouchi N, Sato K et al. (2008) Follistatin-like 1 is an Aktregulated cardioprotective factor that is secreted by the heart. Circulation 117:3099–3108. 10.1161/CIRCULATIONAHA.108.767673 PubMed DOI PMC

Shibanuma M, Mashimo J, Mita A et al. (1993) Cloning from a mouse osteoblastic cell line of a set of transforming-growthfactor-beta 1-regulated genes, one of which seems to encode a follistatin-related polypeptide. Eur J Biochem FEBS 217:13–19 PubMed

Zwijsen A, Blockx H, Van Arnhem W et al. (1994) Characterization of a rat C6 glioma-secreted follistatin-related protein (FRP). Cloning and sequence of the human homologue. Eur J Biochem 225:937–946 PubMed

Sylva M, Moorman AFM, van den Hof MJB (2013) Follistatin-like 1 in vertebrate development: follistatin-like 1 in vertebrate development. Birth Defects Res Part C Embryo Today Rev 99:61–69. 10.1002/bdrc.21030 PubMed DOI

Mattiotti A, Prakash S, Barnett P, van den Hof MJB (2018) Follistatin-like 1 in development and human diseases. Cell Mol Life Sci CMLS 75:2339–2354. 10.1007/s00018-018-2805-0 PubMed DOI PMC

Thierry-Mieg D, Thierry-Mieg J (2006) AceView: A comprehensive cDNA-supported gene and transcripts annotation. Genome Biol 7 Suppl 1:S12.1–14. 10.1186/gb-2006-7-s1-s12 PubMed DOI PMC

Takehara-Kasamatsu Y, Tsuchida K, Nakatani M et al. (2007) Characterization of follistatin-related gene as a negative regulatory factor for activin family members during mouse heart development. J Med Investig JMI 54:276–288 PubMed

Lara-Pezzi E, Felkin LE, Birks EJ et al. (2008) Expression of follistatin-related genes is altered in heart failure. Endocrinology 149:5822–5827. 10.1210/en.2008-0151 PubMed DOI

Oshima Y, Ouchi N, Shimano M et al. (2009) Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation 120:1606–1615. 10.1161/CIRCULATIONAHA.109.872200 PubMed DOI PMC

Shimano M, Ouchi N, Nakamura K et al. (2011) Cardiac myocyte specific ablation of follistatin-like 3 attenuates stress-induced myocardial hypertrophy. J Biol Chem 286:9840–9848. 10.1074/jbc.M110.197079 PubMed DOI PMC

Panse KD, Felkin LE, López-Olañeta MM et al. (2012) Follistatin-like 3 mediates paracrine fibroblast activation by cardiomyocytes. J Cardiovasc Transl Res 5:814–826. 10.1007/s12265-012-9400-9 PubMed DOI

Namdari M, Negahdari B, Cheraghi M et al. (2017) Cardiac failure detection in 30 minutes: new approach based on gold nanoparticles. J Microencapsul 34:132–139. 10.1080/02652048.2017.1296900 PubMed DOI

Shintani T, Kato A, Yuasa-Kawada J et al. (2004) Large-scale identification and characterization of genes with asymmetric expression patterns in the developing chick retina. J Neurobiol 59:34–47. 10.1002/neu.10338 PubMed DOI

Yonehara K, Shintani T, Suzuki R et al. (2008) Expression of SPIG1 reveals development of a retinal ganglion cell subtype projecting to the medial terminal nucleus in the mouse. PLoS ONE 3:e1533. 10.1371/journal.pone.0001533 PubMed DOI PMC

Masuda T, Kai N, Sakuma C et al. (2009) Laser capture microdissection and cDNA array analysis for identification of mouse KIAA/FLJ genes differentially expressed in the embryonic dorsal spinal cord. Brain Res 1249:61–67. 10.1016/j.brainres.2008.10.028 PubMed DOI

GBD (2017) Causes of Death Collaborators (2018) Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Lond Engl 392:1736–1788. 10.1016/S0140-6736(18)32203-7 PubMed DOI PMC

Ling C, Cao S, Kong X (2022) Changes of FSTL1 and MMP-9 levels in patients with acute cerebral infarction and its relationship with hemorrhagic transformation. J Clin Neurosci Of J Neurosurg Soc Australas 99:164–168. 10.1016/j.jocn.2021.10.041 PubMed DOI

Uematsu M, Nakamura K, Nakamura T et al. (2020) Persistent myocardial production of follistatin-like 1 is associated with left ventricular adverse remodeling in patients with myocardial infarction: myocardial production of FSTL1 in AMI patients. J Card Fail 26:733–738. 10.1016/j.cardfail.2020.05.015 PubMed DOI

Gorelik M, Wilson DC, Cloonan YK et al. (2012) Plasma follistatin-like protein 1 is elevated in Kawasaki disease and may predict coronary artery aneurysm formation. J Pediatr 161:116–119. 10.1016/j.jpeds.2012.01.011 PubMed DOI PMC

El-Armouche A, Ouchi N, Tanaka K et al. (2011) Follistatin-like 1 in chronic systolic heart failure: a marker of left ventricular remodeling. Circ Heart Fail 4:621–627. 10.1161/CIRCHEARTFAILURE.110.960625 PubMed DOI PMC

Li B, An J, Feng S, Ge W (2016) Change in serum follistatin-like protein 1 and its clinical significance in children with chronic heart failure. Zhongguo Dang Dai Er Ke Za Zhi PubMed PMC

Cunningham F, Achuthan P, Akanni W et al. (2018) Ensembl 2019. Nucleic Acids Res. 10.1093/nar/gky1113 PubMed DOI PMC

Stelzer G, Rosen N, Plaschkes I et al. (2016) The GeneCards Suite: From gene data mining to disease genome sequence analyses. Curr Protoc Bioinforma 54:1.30.1–1.30.33. 10.1002/cpbi.5 PubMed DOI

Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. cell 116:281–297 PubMed

Sundaram GM, Common JEA, Gopal FE et al. (2013) “Seesaw” expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature 495:103–106. 10.1038/nature11890 PubMed DOI

Altschul SF, Madden TL, Schäfer AA et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402 PubMed PMC

The UniProt Consortium (2017) UniProt: The universal protein knowledgebase. Nucleic Acids Res 45:D158–D169. 10.1093/nar/gkw1099 PubMed DOI PMC

Hambrock HO, Kaufmann B, Müller S et al. (2004) Structural characterization of TSC-36/Flik: analysis of two charge isoforms. J Biol Chem 279:11727–11735. 10.1074/jbc.M309318200 PubMed DOI

Tanaka M, Ozaki S, Osakada F et al. (1998) Cloning of follistatin-related protein as a novel autoantigen in systemic rheumatic diseases. Int Immunol 10:1305–1314 PubMed

Liu T, Qian W-J, Gritsenko MA et al. (2005) Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res 4:2070–2080. 10.1021/pr0502065 PubMed DOI PMC

Sayers EW, Agarwala R, Bolton EE et al. (2019) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 47:D23–D28. 10.1093/nar/gky1069 PubMed DOI PMC

Finn RD, Attwood TK, Babbitt PC et al. (2017) InterPro in 2017-beyond protein family and domain annotations. Nucleic Acids Res 45:D190–D199. 10.1093/nar/gkw1107 PubMed DOI PMC

Keutmann HT, Schneyer AL, Sidis Y (2004) The role of follistatin domains in follistatin biological action. Mol Endocrinol 18:228–240. 10.1210/me.2003-0112 PubMed DOI

Letunic I, Bork P (2018) 20 years of the SMART protein domain annotation resource. Nucleic Acids Res 46:D493–D496. 10.1093/nar/gkx922 PubMed DOI PMC

Schmidt T, Samaras P, Frejno M et al. (2018) ProteomicsDB. Nucleic Acids Res 46:D1271–D1281. 10.1093/nar/gkx1029 PubMed DOI PMC

Bradshaw AD (2012) Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol 44:480–488. 10.1016/j.biocel.2011.12.021 PubMed DOI PMC

Yates B, Braschi B, Gray KA et al. (2017) Genenames.org: the HGNC and VGNC resources in 2017. Nucleic Acids Res 45:D619–D625. 10.1093/nar/gkw1033 PubMed DOI PMC

Wu Y, Zhou S, Smas CM (2010) Downregulated expression of the secreted glycoprotein follistatin-like 1 (Fstl1) is a robust hallmark of preadipocyte to adipocyte conversion. Mech Dev 127:183–202. 10.1016/j.mod.2009.12.003 PubMed DOI PMC

Cheng S, Huang Y, Lou C et al. (2018) FSTL1 enhances chemoresistance and maintains stemness in breast cancer cells via integrin β3/Wnt signaling under miR-137 regulation. Cancer Biol Ther. 10.1080/15384047.2018.1529101 PubMed DOI PMC

Galimov A, Hartung A, Trepp R et al. (2015) Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance. J Mol Med Berl Ger 93:1369–1379. 10.1007/s00109-015-1322-y PubMed DOI PMC

Rosenberg MI, Georges SA, Asawachaicharn A et al. (2006) MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206. J Cell Biol 175:77–85. 10.1083/jcb.200603039 PubMed DOI PMC

Shi D-L, Shi G-R, Xie J et al. (2016) MicroRNA-27a inhibits cell migration and invasion of fibroblast-like synoviocytes by targeting follistatin-like protein 1 in rheumatoid arthritis. Mol Cells 39:611–618. 10.14348/molcells.2016.0103 PubMed DOI PMC

Xiao Y, Zhang Y, Chen Y et al. (2018) Inhibition of microRNA9–5p protects against cardiac remodeling following myocardial infarction in mice. Hum Gene Ther. 10.1089/hum.2018.059 PubMed DOI

Zhang Z-M, Zhang A-R, Xu M et al. (2017) TLR-4/miRNA32–5p/FSTL1 signaling regulates mycobacterial survival and inflammatory responses in Mycobacterium tuberculosis-infected macrophages. Exp Cell Res 352:313–321. 10.1016/j.yexcr.2017.02.025 PubMed DOI

Agarwal V, Bell GW, Nam J-W, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. eLife 4:. 10.7554/eLife.05005 PubMed DOI PMC

Chou C-H, Chang N-W, Shrestha S et al. (2016) miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res 44:D239–D247. 10.1093/nar/gkv1258 PubMed DOI PMC

Mouillet J-F, Mishima T, Pafaro AMDA et al. (2015) The expression and post-transcriptional regulation of FSTL1 transcripts in placental trophoblasts. Placenta 36:1231–1238. 10.1016/j.placenta.2015.09.005 PubMed DOI PMC

Doroudgar S, Glembotski CC (2011) The cardiokine story unfolds: ischemic stress-induced protein secretion in the heart. Trends Mol Med 17:207–214. 10.1016/j.molmed.2010.12.003 PubMed DOI PMC

Ouchi N, Oshima Y, Ohashi K et al. (2008) Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem 283:32802–32811. 10.1074/jbc.M803440200 PubMed DOI PMC

Widera C, Horn-Wichmann R, Kempf T et al. (2009) Circulating concentrations of follistatin-like 1 in healthy individual and patients with acute coronary syndrome as assessed by an immunoluminometric sandwich assay. Clin Chem 55:1794–1800. 10.1373/clinchem.2009.129411 PubMed DOI

Thul PJ, Åkesson L, Wiking M et al. (2017) A subcellular map of the human proteome. Science. 10.1126/science.aal3321 PubMed DOI

Chaly Y, Fu Y, Marinov A et al. (2014) Follistatin-like protein 1 enhances NLRP3 inflammasome-mediated IL-1β secretion from monocytes and macrophages. Eur J Immunol 44:1467–1479. 10.1002/eji.201344063 PubMed DOI PMC

Claros MG, Vincens P (1996) Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241:779–786 PubMed

Emanuelsson O, Nielsen H, Brunak S, von Heijne G (2000) Predicting subcellular localization of proteins based on their N-terminal amino acid sequence. J Mol Biol 300:1005–1016. 10.1006/jmbi.2000.3903 PubMed DOI

Wei K, Serpooshan V, Hurtado C et al. (2015) Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 525:479–485. 10.1038/nature15372 PubMed DOI PMC

Magadum A, Singh N, Kurian AA et al. (2018) Ablation of a single N-glycosylation site in human FSTL 1 induces cardiomyocyte proliferation and cardiac regeneration. Mol Ther Nucleic Acids 13:133–143. 10.1016/j.omtn.2018.08.021 PubMed DOI PMC

Sidis Y (2001) Follistatin: essential role for the N-terminal domain in activin binding and neutralization. J Biol Chem 276:17718–17726. 10.1074/jbc.M100736200 PubMed DOI

Li L, Li X, Liu X et al. (2013) Expression, characterization, and preliminary X-ray crystallographic analysis of recombinant murine follistatin-like 1 expressed in Drosophila S2 cells. Biosci Trends 7:93–100 PubMed

Zhou J, Liao M, Hatta T et al. (2006) Identification of a follistatin-related protein from the tick Haemaphysalis longicornis and its effect on tick oviposition. Gene 372:191–198. 10.1016/j.gene.2005.12.020 PubMed DOI

Tanaka M, Murakami K, Ozaki S et al. (2010) DIP2 discointeracting protein 2 homolog A (Drosophila) is a candidate receptor for follistatin-related protein/follistatin-like 1 - analysis of their binding with TGF-β superfamily proteins: DIP2A is a candidate receptor for FRP/FSTL1. FEBS J 277:4278–4289. 10.1111/j.1742-4658.2010.07816.x PubMed DOI

Geng Y, Dong Y, Yu M et al. (2011) Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Proc Natl Acad Sci 108:7058–7063. 10.1073/pnas.1007293108 PubMed DOI PMC

Li K-C, Zhang F-X, Li C-L et al. (2011) Follistatin-like 1 suppresses sensory afferent transmission by activating Na+, K+-ATPase. Neuron 69:974–987. 10.1016/j.neuron.2011.01.022 PubMed DOI

Murakami K, Tanaka M, Usui T et al. (2012) Follistatin-related protein/follistatin-like 1 evokes an innate immune response via CD14 and toll-like receptor 4. FEBS Lett 586:319–324. 10.1016/j.febslet.2012.01.010 PubMed DOI

Prieto C, De Las RJ (2006) APID: agile protein interaction dataanalyzer. Nucleic Acids Res 34:W298–W302. 10.1093/nar/gkl128 PubMed DOI PMC

Ouchi N, Asaumi Y, Ohashi K et al. (2010) DIP2A functions as a FSTL1 receptor. J Biol Chem 285:7127–7134. 10.1074/jbc.M109.069468 PubMed DOI PMC

Ogura Y, Ouchi N, Ohashi K et al. (2012) Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models. Circulation 126:1728–1738. 10.1161/CIRCULATIONAHA.112.115089 PubMed DOI PMC

Miyabe M, Ohashi K, Shibata R et al. (2014) Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury. Cardiovasc Res 103:111–120. 10.1093/cvr/cvu105 PubMed DOI PMC

Seki M, Powers JC, Maruyama S et al. (2018) Acute and chronic increases of circulating FSTL1 normalize energy substrate metabolism in pacing-induced heart failure. Circ Heart Fail 11:e004486. 10.1161/CIRCHEARTFAILURE.117.004486 PubMed DOI PMC

Shimano M, Ouchi N, Nakamura K et al. (2011) Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload. Proc Natl Acad Sci U S A 108:E899–906. 10.1073/pnas.1108559108 PubMed DOI PMC

Ni S, Li C, Xu N et al. (2018) Follistatin-like protein 1 induction of matrix metalloproteinase 1, 3 and 13 gene expression in rheumatoid arthritis synoviocytes requires MAPK, JAK/STAT3 and NF-κB pathways. J Cell Physiol 234:454–463. 10.1002/jcp.26580 PubMed DOI

Sundaram GM, Ismail HM, Bashir M et al. (2017) EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis. J Exp Med 214:2889–2900. 10.1084/jem.20170354 PubMed DOI PMC

Zhang D, Ma X, Sun W et al. (2015) Down-regulated FSTL5 promotes cell proliferation and survival by affecting Wnt/β-catenin signaling in hepatocellular carcinoma. Int J Clin Exp Pathol 8:3386–3394 PubMed PMC

Miyamae T, Marinov AD, Sowders D et al. (1950) (2006) Follistatin-like protein-1 is a novel proinflammatory molecule. J Immunol Baltim Md 177:4758–4762 PubMed

Wilson DC, Marinov AD, Blair HC et al. (2010) Follistatin-like protein 1 is a mesenchyme-derived inflammatory protein and may represent a biomarker for systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum 62:2510–2516. 10.1002/art.27485 PubMed DOI PMC

Masuda T, Sakuma C, Nagaoka A et al. (2014) Follistatin-like 5 is expressed in restricted areas of the adult mouse brain: implications for its function in the olfactory system. Congenit Anom 54:63–66. 10.1111/cga.12022 PubMed DOI

Karczewski KJ, Weisburd B, Thomas B et al. (2017) The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 45:D840–D845. 10.1093/nar/gkw971 PubMed DOI PMC

Sylva M, Li VSW, Bufng AAA et al. (2011) The BMP antagonist follistatin-like 1 is required for skeletal and lung organogenesis. PLoS ONE 6:e22616. 10.1371/journal.pone.0022616 PubMed DOI PMC

Adams D, Larman B, Oxburgh L (2007) Developmental expression of mouse follistatin-like 1 (Fstl1): dynamic regulation during organogenesis of the kidney and lung. Gene Expr Patterns 7:491–500. 10.1016/j.modgep.2006.10.009 PubMed DOI PMC

Dal-Pra S, Fürthauer M, Van-Celst J et al. (2006) Noggin1 and follistatin-like2 function redundantly to chordin to antagonize BMP activity. Dev Biol 298:514–526. 10.1016/j.ydbio.2006.07.002 PubMed DOI

Liu S, Shen H, Xu M et al. (2010) FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-{kappa}B-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model. Am J Physiol Endocrinol Metab 299:E351–363. 10.1152/ajpendo.00005.2010 PubMed DOI

Okabayashi K, Shoji H, Onuma Y et al. (1999) cDNA cloning and distribution of the Xenopus follistatin-related protein. Biochem Biophys Res Commun 254:42–48. 10.1006/bbrc.1998.9892 PubMed DOI

Suzuki R, Matsumoto M, Fujikawa A et al. (2014) SPIG1 negatively regulates BDNF maturation. J Neurosci Of J Soc Neurosci 34:3429–3442. 10.1523/JNEUROSCI.1597-13.2014 PubMed DOI PMC

Szabo L, Morey R, Palpant NJ et al. (2015) Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biol 16:126. 10.1186/s13059-015-0690-5 PubMed DOI PMC

Chistiakov DA, Orekhov AN, Bobryshev YV (2016) Cardiac extracellular vesicles in normal and infarcted heart. Int J Mol Sci. 10.3390/ijms17010063 PubMed DOI PMC

Li M, Ding W, Sun T et al. (2018) Biogenesis of circular RNAs and their roles in cardiovascular development and pathology. FEBS J 285:220–232. 10.1111/febs.14191 PubMed DOI

van den Berg G, Somi S, Bufng AAM et al. (2007) (2007) Patterns of expression of the follistatin and Follistatin-like1 genes during chicken heart development: a potential role in valvulogenesis and late heart muscle cell formation. Anat Rec Hoboken NJ 290:783–787. 10.1002/ar.20559 PubMed DOI

Kretzschmar K, Post Y, Bannier-Hélaouët M et al. (2018) Profiling proliferative cells and their progeny in damaged murine hearts. Proc Natl Acad Sci U S A 115:E12245–E12254. 10.1073/pnas.1805829115 PubMed DOI PMC

Wang M, Weiss M, Simonovic M et al. (2012) PaxDb, a database of protein abundance averages across all three domains of life. Mol Cell Proteomics MCP 11:492–500. 10.1074/mcp.O111.014704 PubMed DOI PMC

Wu C, Jin X, Tsueng G et al. (2016) BioGPS: building your own mash-up of gene annotations and expression profiles. Nucleic Acids Res 44:D313–316. 10.1093/nar/gkv1104 PubMed DOI PMC

Stylianidis V, Hermans KCM, Blankesteijn WM (2017) Wnt signaling in cardiac remodeling and heart failure. Handb Exp Pharmacol 243:371–393. 10.1007/164_2016_56 PubMed DOI

Prakash S, Borreguero LJJ, Sylva M et al. (2017) Deletion of Fstl1 (follistatin-Like 1) from the endocardial/endothelial lineage causes mitral valve disease. Arterioscler Thromb Vasc Biol 37:e116–e130. 10.1161/ATVBAHA.117.309089 PubMed DOI

Prakash S, Mattiotti A, Sylva M et al. (2019) Identifying pathogenic variants in the follistatin-like 1 gene (FSTL1) in patients with skeletal and atrioventricular valve disorders. Mol Genet Genomic Med e567. 10.1002/mgg3.567 PubMed DOI PMC

Maruyama S, Nakamura K, Papanicolaou KN et al. (2016) Follistatin-like 1 promotes cardiac fbroblast activation and protects the heart from rupture. EMBO Mol Med 8:949–966. 10.15252/emmm.201506151 PubMed DOI PMC

Tanaka K, Valero-Muñoz M, Wilson RM et al. (2016) Follistatin like 1 regulates hypertrophy in heart failure with preserved ejection fraction. JACC Basic Transl Sci 1:207–221. 10.1016/j.jacbts.2016.04.002 PubMed DOI PMC

Widera C, Giannitsis E, Kempf T et al. (2012) Identification of follistatin-like 1 by expression cloning as an activator of the growth differentiation factor 15 gene and a prognostic biomarker in acute coronary syndrome. Clin Chem 58:1233–1241. 10.1373/clinchem.2012.182816 PubMed DOI PMC

Aikawa T, Shimada K, Miyauchi K et al. (2019) Associations among circulating levels of follistatin-like 1, clinical parameters, and cardiovascular events in patients undergoing elective percutaneous coronary intervention with drug-eluting stents. PLoS ONE 14:e0216297. 10.1371/journal.pone.0216297 PubMed DOI PMC

Lee S-Y, Kim D-Y, Kyung Kwak M et al. (2019) High circulating follistatin-like protein 1 as a biomarker of a metabolically unhealthy state. Endocr J. 10.1507/endocrj.EJ18-0352 PubMed DOI

Xi Y, Gong D-W, Tian Z (2016) FSTL1 as a potential mediator of exercise-induced cardioprotection in post-myocardial infarction rats. Sci Rep 6:32424. 10.1038/srep32424 PubMed DOI PMC

Hayakawa S, Ohashi K, Shibata R et al. (2015) Cardiac myocyte derived follistatin-like 1 prevents renal injury in a subtotal nephrectomy model. J Am Soc Nephrol JASN 26:636–646. 10.1681/ASN.2014020210 PubMed DOI PMC

Philipp U, Vollmar A, Häggström J et al. (2012) Multiple loci are associated with dilated cardiomyopathy in Irish wolfhounds. PLoS ONE 7:e36691. 10.1371/journal.pone.0036691 PubMed DOI PMC

Stern JA, Hsue W, Song K-H et al. (2015) Severity of mitral valve degeneration is associated with chromosome 15 loci in Whippet dogs. PLoS ONE 10:e0141234. 10.1371/journal.pone.0141234 PubMed DOI PMC

Divers J, Palmer ND, Langefeld CD et al. (2017) Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes. BMC Genet 18:105. 10.1186/s12863-017-0572-9 PubMed DOI PMC

Guo Y, Tomlinson B, Chu T et al. (2012) A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits. PLoS ONE 7:e31489. 10.1371/journal.pone.0031489 PubMed DOI PMC

Schriml LM, Mitraka E, Munro J et al. (2019) Human Disease Ontology 2018 update: classification, content and workflow expansion. Nucleic Acids Res 47:D955–D962. 10.1093/nar/gky1032 PubMed DOI PMC

Maruyama S, Nakamura K, Papanicolaou KN et al. (2016) Follistatin‐like 1 promotes cardiac fibroblast activation and protects the heart from rupture. EMBO Mol Med 8:949–966. 10.15252/emmm.201506151 PubMed DOI PMC

Tuunanen H, Ukkonen H, Knuuti J (2008) Myocardial fatty acid metabolism and cardiac performance in heart failure. Curr Cardiol Rep 10:142–148 PubMed

Le Luduec JB, Condamine T, Louvet C et al. (2008) An immunomodulatory role for follistatin-like 1 in heart allograft transplantation. Am J Transplant Of J Am Soc Transplant Am Soc Transpl Surg 8:2297–2306. 10.1111/j.1600-6143.2008.02398.x PubMed DOI

Shen H, Cui G, Li Y et al. (2019) Follistatin-like 1 protects mesenchymal stem cells from hypoxic damage and enhances their therapeutic efficacy in a mouse myocardial infarction model. Stem Cell Res Ther 10:17. 10.1186/s13287-018-1111-y PubMed DOI PMC

van Wijk B, Gunst QD, Moorman AFM, van den Hof MJB (2012) Cardiac regeneration from activated epicardium. PLoS ONE. 10.1371/journal.pone.0044692 PubMed DOI PMC

Chen W, Xia J, Hu P et al. (2016) Follistatin-like 1 protects cardiomyoblasts from injury induced by sodium nitroprusside through modulating Akt and Smad1/5/9 signaling. Biochem Biophys Res Commun 469:418–423. 10.1016/j.bbrc.2015.12.026 PubMed DOI

Yang W, Duan Q, Zhu X et al. (2019) Follistatin-like 1 attenuates ischemia/reperfusion injury in cardiomyocytes via regulation of autophagy. In: BioMed Res. Int https://www.hindawi.com/journals/bmri/2019/9537382/abs/. Accessed 22 May 2019 PubMed PMC

Li C, Dai L, Zhang J et al. (2018) Follistatin-like protein 5 inhibits hepatocellular carcinoma progression by inducing caspasedependent apoptosis and regulating Bcl-2 family proteins. J Cell Mol Med 22:6190–6201. 10.1111/jcmm.13906 PubMed DOI PMC

Nakamura M, Sadoshima J (2018) Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15:387–407. 10.1038/s41569-018-0007-y PubMed DOI

Rubattu S, Forte M, Marchitti S, Volpe M (2019) Molecular implications of natriuretic peptides in the protection from hypertension and target organ damage development. Int J Mol Sci. 10.3390/ijms20040798 PubMed DOI PMC

Shiojima I, Sato K, Izumiya Y et al. (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108–2118. 10.1172/JCI24682 PubMed DOI PMC

Talman V, Ruskoaho H (2016) Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res 365:563–581. 10.1007/s00441-016-2431-9 PubMed DOI PMC

Frangogiannis NG (2015) Inflammation in cardiac injury, repair and regeneration. Curr Opin Cardiol 30:240–245. 10.1097/HCO.0000000000000158 PubMed DOI PMC

Winbanks CE, Chen JL, Qian H et al. (2013) The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol 203:345–357. 10.1083/jcb.201211134 PubMed DOI PMC

Bergmann O (2019) Clearing up the mist: cardiomyocyte renewal in human hearts. Eur Heart J 40:1037–1038. 10.1093/eurheartj/ehz097 PubMed DOI

Bergmann O, Zdunek S, Felker A et al. (2015) Dynamics of cell generation and turnover in the human heart. Cell 161:1566–1575. 10.1016/j.cell.2015.05.026 PubMed DOI

DeLeon-Pennell KY, Meschiari CA, Jung M, Lindsey ML (2017) Matrix metalloproteinases in myocardial infarction and heart failure. Prog Mol Biol Transl Sci 147:75–100. 10.1016/bs.pmbts.2017.02.001 PubMed DOI PMC

Chan QKY, Ngan HYS, Ip PPC et al. (2009) Tumor suppressor effect of follistatin-like 1 in ovarian and endometrial carcinogenesis: a differential expression and functional analysis. Carcinogenesis 30:114–121. 10.1093/carcin/bgn215 PubMed DOI

Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5:15. 10.1186/1755-1536-5-15 PubMed DOI PMC

Hu P-F, Ma C-Y, Sun F-F et al. (2019) Follistatin-like protein 1 (FSTL1) promotes chondrocyte expression of matrix metalloproteinase and inflammatory factors via the NF-κB pathway. J Cell Mol Med 23:2230–2237. 10.1111/jcmm.14155 PubMed DOI PMC

Kawabata D, Tanaka M, Fujii T et al. (2004) Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis. Arthritis Rheum 50:660–668. 10.1002/art.20023 PubMed DOI

Liu Y, Wei J, Zhao Y et al. (2017) Follistatin-like protein 1 promotes inflammatory reactions in nucleus pulposus cells by interacting with the MAPK and NFκB signaling pathways. Oncotarget 8:43023–43034. 10.18632/oncotarget.17400 PubMed DOI PMC

Ni X, Cao X, Wu Y, Wu J (2018) FSTL1 suppresses tumor cell proliferation, invasion and survival in non-small cell lung cancer. Oncol Rep 39:13–20. 10.3892/or.2017.6061 PubMed DOI PMC

Tanaka M, Ozaki S, Kawabata D et al. (2003) Potential preventive effects of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis. Int Immunol 15:71–77. 10.1093/intimm/dxg005 PubMed DOI

Zabala W, Cruz R, Barreiro-de Acosta M et al. (2013) New genetic associations in thiopurine-related bone marrow toxicity among inflammatory bowel disease patients. Pharmacogenomics 14:631–640. 10.2217/pgs.13.38 PubMed DOI

Rosano GM, Vitale C (2018) Metabolic modulation of cardiac metabolism in heart failure. Card Fail Rev 4:99–103. 10.15420/cfr.2018.18.2 PubMed DOI PMC

Li F, Zhang K, Xu T et al. (2019) Exosomal microRNA-29a mediates cardiac dysfunction and mitochondrial inactivity in obesityrelated cardiomyopathy. Endocrine 63:480–488. 10.1007/s12020-018-1753-7 PubMed DOI

Coronado MJ, Bruno KA, Blauwet LA et al. (2019) Elevated Sera sST2 is associated with heart failure in men ≤50 years old with myocarditis. J Am Heart Assoc 8:e008968. 10.1161/JAHA.118.008968 PubMed DOI PMC

Li W, Alahdal M, Deng Z et al. (2020) Molecular functions of FSTL1 in the osteoarthritis. Int Immunopharmacol 83:106465. 10.1016/j.intimp.2020.106465 PubMed DOI