{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:02:38Z","timestamp":1792803758840,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,18]],"date-time":"2023-02-18T00:00:00Z","timestamp":1676678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research and Development Fund, Faculty of Science, University of Technology Sydney","id":[{"id":"https:\/\/ror.org\/03f0f6041","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Australian Government Research Training Program (RTP) Stipend","id":[{"id":"https:\/\/ror.org\/0314h5y94","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation. Thus, in this study, we investigated\u2014for the first time\u2014FKBPL\u2019s role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and\/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p &lt; 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p &lt; 0.01\u20130.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p &lt; 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p &lt; 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF.<\/jats:p>","DOI":"10.3390\/biom13020395","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T03:56:07Z","timestamp":1676865367000},"page":"395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["FK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility"],"prefix":"10.3390","volume":"13","author":[{"given":"Michael","family":"Chhor","sequence":"first","affiliation":[{"name":"Faculty of Science, School of Life Sciences, University of Technology Sydney, Broadway, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, University of Technology Sydney, Broadway, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-6557","authenticated-orcid":false,"given":"Djurdja","family":"Jeroti\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3758-3719","authenticated-orcid":false,"given":"Milorad","family":"Te\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"},{"name":"Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina N.","family":"Nikoli\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, University of Nis, 18000 Nis, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Pavlovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2014Cardiology, Faculty of Medicine, University of Nis, 18000 Nis, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rada M.","family":"Vu\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of Cardiology, Clinical Centre of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3446-2241","authenticated-orcid":false,"given":"Benjamin","family":"Rayner","sequence":"additional","affiliation":[{"name":"Inflammation Group, Heart Research Institute, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J.","family":"Watson","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ledwidge","sequence":"additional","affiliation":[{"name":"STOP-HF Unit, St. Vincent\u2019s University Hospital, D04 T6F4 Dublin, Ireland"},{"name":"School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"McDonald","sequence":"additional","affiliation":[{"name":"STOP-HF Unit, St. Vincent\u2019s University Hospital, D04 T6F4 Dublin, Ireland"},{"name":"School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Robson","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-3929","authenticated-orcid":false,"given":"Kristine C.","family":"McGrath","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, University of Technology Sydney, Broadway, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"McClements","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, University of Technology Sydney, Broadway, NSW 2007, Australia"},{"name":"Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,18]]},"reference":[{"key":"ref_1","unstructured":"Malik, A., Brito, D., Vaqar, S., and Chhabra, L. (2022). Congestive Heart Failure, StatPearls."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1001\/jama.2020.13310","article-title":"Heart Failure","volume":"324","author":"Baman","year":"2020","journal-title":"JAMA"},{"key":"ref_3","unstructured":"Australian Institute of Health and Welfare (2023, February 13). Heart, Stroke and Vascular Disease: Australian Facts, Available online: https:\/\/www.aihw.gov.au\/reports\/heart-stroke-vascular-diseases\/hsvd-facts\/contents\/about."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4901","DOI":"10.1093\/eurheartj\/ehab670","article-title":"2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Developed by the Task Force for the diagno-sis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Inamdar, A.A., and Inamdar, A.C. (2016). Heart Failure: Diagnosis, Management and Utilization. J. Clin. Med., 5.","DOI":"10.3390\/jcm5070062"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"200009","DOI":"10.1183\/16000617.0009-2020","article-title":"BNP\/NT-proBNP in pulmonary arterial hypertension: Time for point-of-care testing?","volume":"29","author":"Lewis","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.acvd.2021.10.007","article-title":"Evaluation of the diagnostic accuracy of current biomarkers in heart failure with preserved ejection fraction: A systematic review and meta-analysis","volume":"114","author":"Chen","year":"2021","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13145","DOI":"10.1038\/s41598-019-49511-4","article-title":"Association between Galectin-3 levels within central and peripheral venous blood, and adverse left ventricular remodelling after first acute myocardial infarction","volume":"9","author":"Andrejic","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Annett, S., Spence, S., Garciarena, C., Campbell, C., Dennehy, M., Drakeford, C., Lai, J., Dowling, J., Moore, G., and Yakkundi, A. (2021). The immunophilin protein FKBPL and its peptide derivatives are novel regulators of vascular integrity and inflammation via NF-\u03baB signaling. bioRxiv.","DOI":"10.1101\/2021.02.24.431422"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1161\/ATVBAHA.114.304539","article-title":"FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis","volume":"35","author":"Yakkundi","year":"2015","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3389\/fendo.2021.650328","article-title":"FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function","volume":"12","author":"Alqudah","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-78676-6","article-title":"FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease","volume":"10","author":"Januszewski","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41416-019-0649-5","article-title":"FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer","volume":"122","author":"Annett","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chen, H., Tesic, M., Nikolic, V.N., Pavlovic, M., Vucic, R.M., Spasic, A., Jovanovic, H., Jovanovic, I., Town, S.E.L., and Padula, M.P. (2022). Systemic Biomarkers and Unique Pathways in Different Phenotypes of Heart Failure with Preserved Ejection Fraction. Biomolecules, 12.","DOI":"10.3390\/biom12101419"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1161\/CIRCULATIONAHA.107.728550","article-title":"Diastolic stiffness of the failing diabetic heart: Importance of fibrosis, advanced glycation end products, and myocyte resting tension","volume":"117","author":"Hamdani","year":"2008","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s11626-010-9368-1","article-title":"The H9C2 cell line and primary neonatal cardiomyocyte cells show similar hypertrophic responses in vitro","volume":"47","author":"Watkins","year":"2011","journal-title":"Vitr. Cell. Dev. Biol. Anim."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1091\/mbc.E16-01-0038","article-title":"Biology of the cardiac myocyte in heart disease","volume":"27","author":"Peter","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_20","unstructured":"Nakano, S., Muramatsu, T., Nishimura, S., and Senbonmatsu, T. (2012). Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues\u2014From Molecules to Humans, IntechOpen."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1136\/postgradmedj-2016-134045","article-title":"The renin-angiotensin-aldosterone system in heart failure for the non-specialist: The past, the present and the future","volume":"93","author":"Orsborne","year":"2016","journal-title":"Postgrad. Med. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.1002\/ehf2.13626","article-title":"Cardiac remodelling predicts outcome in patients with chronic heart failure","volume":"8","author":"Xu","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1210\/clinem\/dgaa403","article-title":"Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment","volume":"106","author":"Todd","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yakkundi, A., McCallum, L., O\u2019Kane, A., Dyer, H., Worthington, J., McKeen, H.D., McClements, L., Elliott, C., McCarthy, H., and Hirst, D.G. (2013). The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055075"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fcvm.2019.00015","article-title":"Microvascular Rarefaction and Heart Failure With Preserved Ejection Fraction","volume":"6","author":"Zeng","year":"2019","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1093\/eurjhf\/hft077","article-title":"Galectin-3 in heart failure with preserved ejection fraction","volume":"15","author":"Edelmann","year":"2013","journal-title":"Eur. J. Heart Fail."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/1440-1681.13048","article-title":"The role of galectin-3 in heart failure and cardiovascular disease","volume":"46","author":"Zhong","year":"2018","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"613123","DOI":"10.3389\/fcvm.2020.613123","article-title":"Effects of Cardiomyocyte-Specific Deletion of STAT3\u2013A Murine Model of Heart Failure With Preserved Ejection Fraction","volume":"7","author":"Zhao","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1056\/NEJMoa025050","article-title":"Coronary Microvascular Dysfunction and Prognosis in Hypertrophic Cardiomyopathy","volume":"349","author":"Cecchi","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e021936","DOI":"10.1161\/JAHA.120.021936","article-title":"Prognostic Value of Transthoracic Doppler Echocardiography Coronary Flow Velocity Reserve in Patients With Asymmetric Hypertrophic Cardiomyopathy","volume":"10","author":"Tesic","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2967\/jnumed.111.096156","article-title":"PET\/CT Assessment of Symptomatic Individuals with Obstructive and Nonobstructive Hypertrophic Cardiomyopathy","volume":"53","author":"Bravo","year":"2012","journal-title":"J. Nucl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s12968-014-0049-1","article-title":"Coronary microvascular ischemia in hypertrophic cardiomyopathy\u2014A pixel-wise quantitative cardiovascular magnetic resonance perfusion study","volume":"16","author":"Ismail","year":"2014","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yang, Y., Li, Z., Guo, X., Zhou, Y., Chang, Y., Yang, H., Yu, S., Ouyang, N., Chen, S., and Sun, G. (2022). Interventricular Septum Thickness for the Prediction of Coronary Heart Disease and Myocardial Infarction in Hypertension Population: A Prospective Study. J. Clin. Med., 11.","DOI":"10.3390\/jcm11237152"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/01.CIR.60.5.1058","article-title":"Interventricular septal thickness and left ventricular hypertrophy. An echocardiographic study","volume":"60","author":"Kansal","year":"1979","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1001\/jama.2013.7588","article-title":"Natriuretic peptide-based screening and collaborative care for heart failure: The STOP-HF randomized trial","volume":"310","author":"Ledwidge","year":"2013","journal-title":"JAMA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1002\/ehf2.13320","article-title":"Multiplexed measurement of candidate blood protein biomarkers of heart failure","volume":"8","author":"Tonry","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12967-021-02735-3","article-title":"Biomarker profiling for risk of future heart failure (HFpEF) development","volume":"19","author":"Watson","year":"2021","journal-title":"J. Transl. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/395\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:36:13Z","timestamp":1760121373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,18]]},"references-count":37,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["biom13020395"],"URL":"https:\/\/doi.org\/10.3390\/biom13020395","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,18]]}}}