The secretome as a biomarker and functional agent in heart failure

Abstract

Heart failure (HF) is a complex and multifactorial disease. Recent advances have been made in understanding the underlying molecular processes involved in HF pathogenesis. These scientific advancements have brought to light the importance of the secretome. This paper presents a thorough overview of the state of science regarding the secretome's involvement in the onset, progression, and possibility of improved diagnosis and therapeutic interventions in HF. We explore the various types of secreted factors, including novel proteins, growth factors, cytokines, and microRNAs. We also discuss how they affect cellular signaling, angiogenesis, fibrosis, pathological cardiac remodeling, and inflammation in HF. Furthermore, we examine the role of the secretome in cardioprotection and cardiotoxicity. This review emphasizes the potential of the secretome for biomarker discovery. This might enable better HF diagnosis, risk stratification, monitoring and treatment. The review also discusses the difficulties on investigating the role of secreted factors and novel directions on secretome research. It highlights its potential as a target for novel therapeutic approaches and biomarker development.

Keywords

Secretome / circulating protein / circulating microRNA / heart failure / biomarker

References

[1] World Health Organization. Cardiovascular diseases (CVDs). Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) [Last accessed on 7 June 2023]

[2] Bragazzi NL,Shu J.Burden of heart failure and underlying causes in 195 countries and territories from 1990 to 2017.Eur J Prev Cardiol2021;28:1682-90

[3] Malik A,Vaqar S. Congestive Heart Failure. StatPearls. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430873/ [Last accessed on 7 June 2023]

[4] Dewey CM,Ponce JM,Grueter CE.Cardiac-secreted factors as peripheral metabolic regulators and potential disease biomarkers.J Am Heart Assoc2016;5:e003101 PMCID:PMC4937259

[5] Uhlén M,Hober A.The human secretome.Sci Signal2019;12:aaz0274

[6] Schulte C,Blankenberg S.Diagnostic and prognostic value of circulating microRNAs in heart failure with preserved and reduced ejection fraction.World J Cardiol2015;7:843-60 PMCID:PMC4691811

[7] Stastna M.Investigating the secretome: lessons about the cells that comprise the heart.Circ Cardiovasc Genet2012;5:o8-18 PMCID:PMC3282018

[8] Blackwood EA,Stastna M.Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response.J Mol Cell Cardiol2020;143:132-44 PMCID:PMC8597053

[9] Harouki N,Remy-Jouet I.The IL-1β antibody gevokizumab limits cardiac remodeling and coronary dysfunction in rats with heart failure.JACC Basic Transl Sci2017;2:418-30 PMCID:PMC6034492

[10] Schumacher SM.Tumor necrosis factor-α in heart failure: an updated review.Curr Cardiol Rep2018;20:117 PMCID:PMC6311126

[11] Azevedo PS,Minicucci MF,Zornoff LA.Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment.Arq Bras Cardiol2016;106:62-9 PMCID:PMC4728597

[12] Cox EJ.A systematic review of fetal genes as biomarkers of cardiac hypertrophy in rodent models of diabetes.PLoS One2014;9:e92903 PMCID:PMC3963983

[13] Jeffrey DA,Garcia AM.Serum circulating proteins from pediatric patients with dilated cardiomyopathy cause pathologic remodeling and cardiomyocyte stiffness.JCI Insight2021;6:e148637 PMCID:PMC8525651

[14] Liu Z,Li L.SERCA2a: a key protein in the Ca²⁺ cycle of the heart failure.Heart Fail Rev2020;25:523-35

[15] Vigil-Garcia M,Eding JEC.Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling.Cardiovasc Res2021;117:1532-45 PMCID:PMC8152696

[16] Razeghi P,Alcorn JL,Frazier OH.Metabolic gene expression in fetal and failing human heart.Circulation2001;104:2923-31

[17] Rajabi M,Razeghi P.Return to the fetal gene program protects the stressed heart: a strong hypothesis.Heart Fail Rev2007;12:331-43

[18] Shimano M,Walsh K.Cardiokines: recent progress in elucidating the cardiac secretome.Circulation2012;126:e327-32

[19] Vassiliadis E,Didangelos A.Novel cardiac-specific biomarkers and the cardiovascular continuum.Biomark Insights2012;7:45-57 PMCID:PMC3347891

[20] Xu D,Fan B.MicroRNAs in extracellular vesicles: Sorting mechanisms, diagnostic value, isolation, and detection technology.Front Bioeng Biotechnol2022;10:948959 PMCID:PMC9618890

[21] Garcia-Martin R,Brandão BB.MicroRNA sequence codes for small extracellular vesicle release and cellular retention.Nature2022;601:446-51 PMCID:PMC9035265

[22] Albanese M,Hüls C.MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells.PLoS Genet2021;17:e1009951 PMCID:PMC8675925

[23] Robert AW,Dallagiovanna B.Secretome analysis performed during in vitro cardiac differentiation: discovering the cardiac microenvironment.Front Cell Dev Biol2020;8:49 PMCID:PMC7025591

[24] Srivastava H,Lau E.Defining the roles of cardiokines in human aging and age-associated diseases.Front Aging2022;3:884321 PMCID:PMC9261440

[25] Sudoh T,Minamino N.A new natriuretic peptide in porcine brain.Nature1988;332:78-81

[26] Mukoyama M,Hosoda K.Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide.J Clin Invest1991;87:1402-12 PMCID:PMC295184

[27] Ichiki T.A new signal from B-type natriuretic peptide in ST-elevation myocardial infarction: what does it mean for B-type natriuretic peptide and innovative diagnostics?.Circulation2010;122:229-32

[28] George J.Chapter 31 - Natriuretic peptides. In: Comprehensive hypertension. Amsterdam: Elsevier 2007. pp. 349-62.

[29] Cao Z,Zhu B.BNP and NT-proBNP as diagnostic biomarkers for cardiac dysfunction in both clinical and forensic medicine.Int J Mol Sci2019;20:1820 PMCID:PMC6515513

[30] Weber M.Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine.Heart2006;92:843-9 PMCID:PMC1860679

[31] Potter LR,Flora DR,Dickey DM.Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications.Handb Exp Pharmacol2009;191:341-66 PMCID:PMC4855512

[32] Holtwick R,Skryabin BV.Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A.J Clin Invest2003;111:1399-407 PMCID:PMC154444

[33] Lainchbury JG,Strangman KM.N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-assisted treatment to lessen serial cardiac readmissions and death) trial.J Am Coll Cardiol2009;55:53-60

[34] Siriwardena M,Ruygrok P.B-type natriuretic peptide signal peptide circulates in human blood: evaluation as a potential biomarker of cardiac ischemia.Circulation2010;122:255-64

[35] Seidelmann SB,Claggett B.An NPPB promoter polymorphism associated with elevated N-terminal pro-B-type natriuretic peptide and lower blood pressure, hypertension, and mortality.J Am Heart Assoc2017;6:e005257 PMCID:PMC5533018

[36] Sangaralingham SJ,Cannone V,Burnett JC.Natriuretic peptide pathways in heart failure: further therapeutic possibilities.Cardiovasc Res2023;118:3416-33 PMCID:PMC9897690

[37] Suzuki T,Yazaki Y.The role of the natriuretic peptides in the cardiovascular system.Cardiovasc Res2001;51:489-94

[38] Brandt RR,Redfield MM.Atrial natriuretic peptide in heart failure.J Am Coll Cardiol1993;22:86A-92A

[39] Tanajak P,Chattipakorn N.Effects of fibroblast growth factor 21 on the heart.J Endocrinol2015;227:R13-30

[40] Beenken A.The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov2009;8:235-53 PMCID:PMC3684054

[41] Keinicke H,Mentzel CMJ.FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation.Endocr Connect2020;9:755-68 PMCID:PMC7424338

[42] Coskun T,Schneider MA.Fibroblast growth factor 21 corrects obesity in mice.Endocrinology2008;149:6018-27

[43] Joki Y,Yuasa D.FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism.Biochem Biophys Res Commun2015;459:124-30

[44] Planavila A,Hondares E.Fibroblast growth factor 21 protects against cardiac hypertrophy in mice.Nat Commun2013;4:2019

[45] Tao J,Huang Y.Sfrp1 protects against acute myocardial ischemia (AMI) injury in aged mice by inhibiting the Wnt/β-catenin signaling pathway.J Cardiothorac Surg2021;16:12 PMCID:PMC7814560

[46] Liu SQ,Kharitonenkov A.Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue.Sci Rep2013;3:2767 PMCID:PMC3783882

[47] Yan B,Yan C.Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: a meta-analysis.Front Endocrinol2023;14:1108234 PMCID:PMC10011636

[48] Wu G,Yan J.Fibroblast growth factor 21 predicts short-term prognosis in patients with acute heart failure: a prospective cohort study.Front Cardiovasc Med2022;9:834967 PMCID:PMC8965840

[49] Sommakia S,Lee SH.FGF21 (fibroblast growth factor 21) defines a potential cardiohepatic signaling circuit in end-stage heart failure.Circ Heart Fail2022;15:e008910

[50] Poniatowski ŁA,Gasik R.Transforming growth factor Beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications.Mediators Inflamm2015;2015:137823 PMCID:PMC4325469

[51] Rochette L,Zeller M,Vergely C.GDF15 and cardiac cells: current concepts and new insights.Int J Mol Sci2021;22:8889 PMCID:PMC8396208

[52] Wang J,Yang X.Roles of growth differentiation factor 15 in atherosclerosis and coronary artery disease.J Am Heart Assoc2019;8:e012826 PMCID:PMC6755840

[53] Wollert KC,Wallentin L.Growth differentiation factor 15 as a biomarker in cardiovascular disease.Clin Chem2017;63:140-51

[54] Rochette L,Cottin Y.Insights into mechanisms of gdf15 and receptor gfral: therapeutic targets.Trends Endocrinol Metab2020;31:939-51

[55] Li M,Cai YL.Growth differentiation factor-15 is associated with cardiovascular outcomes in patients with coronary artery disease.Cardiovasc Diabetol2020;19:120 PMCID:PMC7398317

[56] Chang JY,Kang SG,Zhang BY.The role of growth differentiation factor 15 in energy metabolism.Diabetes Metab J2020;44:363-71 PMCID:PMC7332323

[57] Loffredo FS,Jay SM.Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.Cell2013;153:828-39 PMCID:PMC3677132

[58] Chen L,Liu Y.Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity.Cell Death Dis2021;12:665 PMCID:PMC8253774

[59] Olson KA,Heidecker B.Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts.Eur Heart J2015;36:3426-34 PMCID:PMC4685178

[60] Wells L,Bernstein SI.Myosin heavy chain isoforms regulate muscle function but not myofibril assembly.EMBO J1996;15:4454-9

[61] Gollapudi S,Chandra M.Striated muscle dynamics. In: Reference module in biomedical sciences. Amsterdam: Elsevier: 2014.

[62] Nakao K,Roden R,Leinwand LA.Myosin heavy chain gene expression in human heart failure.J Clin Invest1997;100:2362-70 PMCID:PMC508434

[63] Léger JO,Ming T.Assay of serum cardiac myosin heavy chain fragments in patients with acute myocardial infarction: determination of infarct size and long-term follow-up.Am Heart J1990;120:781-90

[64] Löfberg M,Härkönen M.Myosin heavy-chain fragments and cardiac troponins in the serum in rhabdomyolysis. Diagnostic specificity of new biochemical markers.Arch Neurol1995;52:1210-4

[65] Biering-Sørensen T,Claggett B.Cardiac myosin activator omecamtiv mecarbil improves left ventricular myocardial deformation in chronic heart failure: The COSMIC-HF trial.Circ Heart Fail2020;13:e008007

[66] Sproston NR.Role of C-reactive protein at sites of inflammation and infection.Front Immunol2018;9:754 PMCID:PMC5908901

[67] Sun H,Ichikawa T.C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.Am J Pathol2005;167:1139-48

[68] Ouchi N,Funahashi T.Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue.Circulation2003;107:671-4

[69] Dong Q.Expression of C-reactive protein by alveolar macrophages.J Immunol1996;156:4815-20

[70] Venugopal SK,Yuhanna I,Jialal I.Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells.Circulation2002;106:1439-41

[71] Joshi MS,Cook AC.Increased myocardial prevalence of C-reactive protein in human coronary heart disease: direct effects on microvessel density and endothelial cell survival.Cardiovasc Pathol2012;21:428-35 PMCID:PMC3899797

[72] Sheikh AS,Sheikh NS.C-reactive protein as a predictor of adverse outcome in patients with acute coronary syndrome.Heart Views2012;13:7-12 PMCID:PMC3385197

[73] Grootaert MOJ.Vascular smooth muscle cells in atherosclerosis: time for a re-assessment.Cardiovasc Res2021;117:2326-39 PMCID:PMC8479803

[74] Sharma S,Makan J.Cardiac troponins.J Clin Pathol2004;57:1025-6 PMCID:PMC1770452

[75] Collinson PO,Gaze DC.Measurement of cardiac troponins.Ann Clin Biochem2001;38:423-49

[76] Layland J,Shah AM.Regulation of cardiac contractile function by troponin I phosphorylation.Cardiovasc Res2005;66:12-21

[77] Setsuta K,Ogawa T,Miyatake Y.Use of cytosolic and myofibril markers in the detection of ongoing myocardial damage in patients with chronic heart failure.Am J Med2002;113:717-22

[78] Ueda T.HMGB proteins and transcriptional regulation.Biochim Biophys Acta Biomembr2010;1799:114-8

[79] Pellegrini L,Pontemezzo E,Russo MA.HMGB1 and repair: focus on the heart.Pharmacol Ther2019;196:160-82

[80] Zhang C,Ding W.High-mobility group box 1 (HMGB1) impaired cardiac excitation-contraction coupling by enhancing the sarcoplasmic reticulum (SR) Ca²⁺ leak through TLR4-ROS signaling in cardiomyocytes.J Mol Cell Cardiol2014;74:260-73

[81] Wahid A,Wang X.High-mobility group box 1 serves as an inflammation driver of cardiovascular disease.Biomed Pharmacother2021;139:111555

[82] Kohno T,Naito K.Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling.Cardiovasc Res2009;81:565-73

[83] Yu P,Zhang B.Cardiomyocyte-restricted high-mobility group box 1 (HMGB1) deletion leads to small heart and glycolipid metabolic disorder through GR/PGC-1α signalling.Cell Death Discov2020;6:106 PMCID:PMC7575537

[84] Raucci A,Scavello F,Bianchi ME.The Janus face of HMGB1 in heart disease: a necessary update.Cell Mol Life Sci2019;76:211-29 PMCID:PMC6339675

[85] Andrassy M,Igwe JC.High-mobility group box-1 in ischemia-reperfusion injury of the heart.Circulation2008;117:3216-26

[86] Li W,Wang H.Role of HMGB1 in cardiovascular diseases.Curr Opin Pharmacol2006;6:130-5 PMCID:PMC1782046

[87] Liang CJ,Chang YW,Lin WH.SFRPs Are biphasic modulators of Wnt-signaling-elicited cancer stem cell properties beyond extracellular control.Cell Rep2019;28:1511-25.e5

[88] Surana R,Cai W.Secreted frizzled related proteins: implications in cancers.Biochim Biophys Acta2014;1845:53-65

[89] Gay A.Wnt signaling in cardiovascular disease: opportunities and challenges.Curr Opin Lipidol2017;28:387-96 PMCID:PMC5773247

[90] Pan S,Wang X.Sfrp1 attenuates TAC-induced cardiac dysfunction by inhibiting Wnt signaling pathway- mediated myocardial apoptosis in mice.Lipids Health Dis2018;17:202 PMCID:PMC6114876

[91] Huang A.Role of Sfrps in cardiovascular disease.Ther Adv Chronic Dis2020;11:2040622320901990 PMCID:PMC6987486

[92] Sklepkiewicz P,Kaur R.Loss of secreted frizzled-related protein-1 leads to deterioration of cardiac function in mice and plays a role in human cardiomyopathy.Circ Heart Fail2015;8:362-72 PMCID:PMC4405910

[93] Hao K,Wu H.LncRNA-Safe contributes to cardiac fibrosis through Safe-Sfrp2-HuR complex in mouse myocardial infarction.Theranostics2019;9:7282-97 PMCID:PMC6831303

[94] Wei WY,Zhang WZ.Secreted frizzled-related protein 2 prevents pressure-overload-induced cardiac hypertrophy by targeting the Wnt/β-catenin pathway.Mol Cell Biochem2020;472:241-51 PMCID:PMC7338134

[95] Vatner DE,Zhang J,Vatner SF.Secreted frizzled-related protein 2, a novel mechanism to induce myocardial ischemic protection through angiogenesis.Basic Res Cardiol2020;115:48 PMCID:PMC8530433

[96] Zhang Z,Zhang Z.Secreted frizzled related protein 2 protects cells from apoptosis by blocking the effect of canonical Wnt3a.J Mol Cell Cardiol2009;46:370-7 PMCID:PMC2710029

[97] Mirotsou M,Deb A.Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair.Proc Natl Acad Sci USA2007;104:1643-8 PMCID:PMC1785280

[98] Barandon L,Costet P.Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning.Circ Res2005;96:1299-306

[99] Vigneron F,Lemoine S.GSK-3β at the crossroads in the signalling of heart preconditioning: implication of mTOR and Wnt pathways.Cardiovasc Res2011;90:49-56

[100] Hsueh YC,Gomez JA.The role of Sfrp and DKK proteins in cardiomyocyte development.Physiol Rep2021;9:e14678 PMCID:PMC7883806

[101] Ress C,Goebel G.Circulating Wnt inhibitory factor 1 levels are associated with development of cardiovascular disease.Atherosclerosis2018;273:1-7

[102] Cao M,Li W.Inverse Associations between circulating secreted frizzled related protein 2 (sFRP2) and cardiometabolic risk factors.Front Cardiovasc Med2021;8:723205 PMCID:PMC8551478

[103] Nakamoto M,Miyauchi T,Ozawa M.A new family of heparin binding growth/differentiation factors: differential expression of the midkine (MK) and HB-GAM genes during mouse development.J Biol Chem1992;112:346-9

[104] Mitsiadis TA,Muramatsu T.Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis.Development1995;121:37-51

[105] Muramatsu T.Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases.Proc Jpn Acad Ser B Phys Biol Sci2010;86:410-25 PMCID:PMC3417803

[106] Filippou PS,Constantinidou A.Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target.Oncogene2020;39:2040-54

[107] Jones DR.Measuring midkine: the utility of midkine as a biomarker in cancer and other diseases.Br J Pharmacol2014;171:2925-39 PMCID:PMC4055197

[108] Nakamura E,Yuasa S.Disruption of the midkine gene (Mdk) resulted in altered expression of a calcium binding protein in the hippocampus of infant mice and their abnormal behaviour.Genes Cells1998;3:811-2

[109] Woulfe KC.Midkine's role in cardiac pathology.J Cardiovasc Dev Dis2017;4:13 PMCID:PMC5599136

[110] Kitahara T,Suzuki S.Serum midkine as a predictor of cardiac events in patients with chronic heart failure.J Card Fail2010;16:308-13

[111] Guzel S,Guzel EC.Midkine levels and its relationship with atherosclerotic risk factors in essential hypertensive patients.Niger J Clin Pract2018;21:894-900

[112] Takemoto Y,Harada M.Midkine promotes atherosclerotic plaque formation through its pro-inflammatory, angiogenic and anti-apoptotic functions in apolipoprotein e-knockout mice.Circ J2017;82:19-27

[113] Ishiguro H,Takenaka H.A single intracoronary injection of midkine reduces ischemia/reperfusion injury in swine hearts: a novel therapeutic approach for acute coronary syndrome.Front Physiol2011;2:27. PMCID:PMC3125584

[114] Barnett CF.59 - Pulmonary hypertension due to lung disease. In: Murray and Nadel's textbook of respiratory medicine, 6th ed. 2016. pp. 1050-65.e5.

[115] Bupha-Intr T,Janssen PM.Role of endothelin in the induction of cardiac hypertrophy in vitro.PLoS One2012;7:e43179 PMCID:PMC3422284

[116] Archer CR,Drawnel FM.Endothelin-1 promotes hypertrophic remodelling of cardiac myocytes by activating sustained signalling and transcription downstream of endothelin type A receptors.Cell Signal2017;36:240-54 PMCID:PMC5486433

[117] National Library of Medicine. ECE1 endothelin converting enzyme 1 [Homo sapiens (human)] - Gene - NCBI. Available from: https://www.ncbi.nlm.nih.gov/gene/1889 [Last accessed on 7 June 2023]

[118] Aalto K,Kiss EA.Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer.Blood2011;118:3725-33 PMCID:PMC3833035

[119] Lin CH,Yang KD.Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers.J Formos Med Assoc2021;120:5-24

[120] Ito T,Matsushita Y.Secreted ectodomain of SIGLEC-9 and MCP-1 synergistically improve acute liver failure in rats by altering macrophage polarity.Sci Rep2017;7:44043 PMCID:PMC5358744

[121] Crocker PR,Varki A.Siglecs and their roles in the immune system.Nat Rev Immunol2007;7:255-66

[122] Nigam PK,Kumar A.Sialic acid in cardiovascular diseases.Indian J Clin Biochem2006;21:54-61 PMCID:PMC3453784

[123] Nicoll G,Liu D.Identification and characterization of a novel siglec, siglec-7, expressed by human natural killer cells and monocytes.J Biol Chem1999;274:34089-95

[124] Von Gunten S,Seitz M.Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment.Blood2005;106:1423-31

[125] Schaub A,Vogel M.Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes.Allergy2011;66:1030-7

[126] Kim B.Activation of Nm23-H1 to suppress breast cancer metastasis via redox regulation.Exp Mol Med2021;53:346-57 PMCID:PMC8080780

[127] Mátyási B,Kopper L.The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis.Pathol Oncol Res2020;26:49-61 PMCID:PMC7109179

[128] Zhou Y.Nucleoside diphosphate kinase: a new player in heart failure?.Cardiovasc Res2001;49:7-10

[129] Abu-Taha IH,Hippe HJ.Nucleoside diphosphate kinase-C suppresses cAMP formation in human heart failure.Circulation2017;135:881-97

[130] Lutz S,Hippe HJ,Niroomand F.Plasma membrane-associated nucleoside diphosphate kinase (nm23) in the heart is regulated by beta-adrenergic signaling.Br J Pharmacol2003;140:1019-26 PMCID:PMC1574115

[131] Chistiakov DA,Myasoedova VA,Orekhov AN.Thrombospondins: a role in cardiovascular disease.Int J Mol Sci2017;18:1540 PMCID:PMC5536028

[132] Frolova EG,Blech L.Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload.FASEB J2012;26:2363-73 PMCID:PMC3360147

[133] Cingolani OH,Seo K.Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle.Circ Res2011;109:1410-4 PMCID:PMC3324097

[134] Zhang K,Yin L,Liu Z.Role of thrombospondin-1 and thrombospondin-2 in cardiovascular diseases (Review).Int J Mol Med2020;45:1275-93 PMCID:PMC7138268

[135] Schroen B,Sharma U.Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy.Circ Res2004;95:515-22

[136] Befekadu R,Larsson A.Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction.Cardiol J2019;26:385-93 PMCID:PMC8084374

[137] Schellings MW,Sage EH.Thrombospondins in the heart: potential functions in cardiac remodeling.J Cell Commun Signal2009;3:201-13 PMCID:PMC2778589

[138] Gonzalez-Quesada C,Biernacka A.Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation.Circ Res2013;113:1331-44 PMCID:PMC4408537

[139] Lee CH,Lui DT.Circulating thrombospondin-2 as a novel fibrosis biomarker of nonalcoholic fatty liver disease in type 2 diabetes.Diabetes Care2021;44:2089-97

[140] Kaiser R,Bals R.The role of circulating thrombospondin-1 in patients with precapillary pulmonary hypertension.Respir Res2016;17:96 PMCID:PMC4967340

[141] Lee C,Lui D.Prospective associations of circulating thrombospondin-2 level with heart failure hospitalization, left ventricular remodeling and diastolic function in type 2 diabetes.Cardiovasc Diabetol2022;21:231 PMCID:PMC9637303

[142] Zhang JM.Cytokines, inflammation, and pain.Int Anesthesiol Clin2007;45:27-37 PMCID:PMC2785020

[143] Besse S,Balse E.Early protective role of inflammation in cardiac remodeling and heart failure: focus on TNFα and resident macrophages.Cells2022;11:1249 PMCID:PMC8998130

[144] Feng Y.Toll-like receptors and myocardial inflammation.Int J Inflam2011;2011:170352 PMCID:PMC3182762

[145] Lafuse WP,Rajaram MVS.Role of cardiac macrophages on cardiac inflammation, fibrosis and tissue repair.Cells2020;10:51 PMCID:PMC7824389

[146] Frangogiannis NG.The inflammatory response in myocardial injury, repair, and remodelling.Nat Rev Cardiol2014;11:255-65 PMCID:PMC4407144

[147] Kapadia S,Torre-Amione G,Ma TS.Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration.J Clin Invest1995;96:1042-52 PMCID:PMC286384

[148] Mann DL.Innate immunity and the failing heart: the cytokine hypothesis revisited.Circ Res2015;116:1254-68 PMCID:PMC4380242

[149] Liu L,Chen X.Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis.Mol Biol Rep2012;39:2683-8

[150] Ridker PM,Thuren T.Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med2017;377:1119-31.

[151] Jung M,Iyer RP.IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation.Basic Res Cardiol2017;112:33 PMCID:PMC5575998

[152] Zhou SS,Wang JQ.miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges.Acta Pharmacol Sin2018;39:1073-84 PMCID:PMC6289363

[153] Dirkx E,De Windt LJ.Regulation of fetal gene expression in heart failure.Biochim Biophys Acta2013;1832:2414-24

[154] O'Brien J,Zayed Y.Overview of microRNA biogenesis, mechanisms of actions, and circulation.Front Endocrinol2018;9:402 PMCID:PMC6085463

[155] Jang JH.The role of microRNAs in cell death pathways.Yeungnam Univ J Med2021;38:107-17 PMCID:PMC8016624

[156] Wang J,Richards AM.Overview of microRNAs in cardiac hypertrophy, fibrosis, and apoptosis.Int J Mol Sci2016;17:749 PMCID:PMC4881570

[157] Kwon C,Olson EN.MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling.Proc Natl Acad Sci USA2005;102:18986-91 PMCID:PMC1315275

[158] Zhao Y,Li A.Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.Cell2007;129:303-17

[159] Port JD,Polk J,buttrick PM.Temporal expression of miRNAs and mRNAs in a mouse model of myocardial infarction.Physiol Genomics2011;43:1087-95 PMCID:PMC3217325

[160] Liu X,Jiang C,Cui F.Differential microRNA expression and regulation in the rat model of post-infarction heart failure.PLoS One2016;11:e0160920 PMCID:PMC4978447

[161] Sayed D,Chen IY,Abdellatif M.MicroRNAs play an essential role in the development of cardiac hypertrophy.Circ Res2007;100:416-24

[162] Liu N,Williams AH.microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart.Genes Dev2008;22:3242-54 PMCID:PMC2600761

[163] Matkovich SJ,Tu Y.MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts.Circ Res2010;106:166-75 PMCID:PMC2804031

[164] Sucharov C,Port JD.miRNA expression in the failing human heart: functional correlates.J Mol Cell Cardiol2008;45:185-92 PMCID:PMC2561965

[165] Peterlin A,Petrovič D.The role of microRNAs in heart failure: a systematic review.Front Cardiovasc Med2020;7:161 PMCID:PMC7593250

[166] Shen NN,Fu YP.The microRNA expression profiling in heart failure: a systematic review and meta-analysis.Front Cardiovasc Med2022;9:856358 PMCID:PMC9240229

[167] Sucharov CC,Port JD.Myocardial microRNAs associated with reverse remodeling in human heart failure.JCI Insight2017;2:e89169 PMCID:PMC5256135

[168] Chen X,Ma L.Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases.Cell Res2008;18:997-1006

[169] Jaffe ES,Stein H.Classification of lymphoid neoplasms: the microscope as a tool for disease discovery.Blood2008;112:4384-99 PMCID:PMC2954680

[170] Gallo A,Alevizos I.The majority of microRNAs detectable in serum and saliva is concentrated in exosomes.PLoS One2012;7:e30679 PMCID:PMC3302865

[171] Wang K,Marzolf B.Circulating microRNAs, potential biomarkers for drug-induced liver injury.Proc Natl Acad Sci USA2009;106:4402-7 PMCID:PMC2657429

[172] Mi S,Zhang W.Circulating microRNAs as biomarkers for inflammatory diseases.Microrna2013;2:63-71 PMCID:PMC4092001

[173] Vavassori C,Colombo GI.Circulating microRNAs as novel biomarkers in risk assessment and prognosis of coronary artery disease.Eur Cardiol2022;17:e06 PMCID:PMC8924954

[174] Sucharov CC,Garcia AM.Circulating microRNAs as biomarkers in pediatric heart diseases.Prog Pediatr Cardiol2018;49:50-2

[175] He X,Wang T,Chen XL.Upregulation of Circulating miR-195-3p in Heart Failure.Cardiology2017;138:107-14

[176] McManus DD.Circulating MicroRNAs in cardiovascular disease.Circulation2011;124:1908-10 PMCID:PMC3951832

[177] Ewelina K,Kazimierczyk R.Altered microRNA dynamics in acute coronary syndrome.Postep Kardiol Inter2020;16:287-93 PMCID:PMC7863810

[178] Widera C,Lorenzen JM.Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome.J Mol Cell Cardiol2011;51:872-5

[179] Bye A,Nauman J.Circulating microRNAs predict future fatal myocardial infarction in healthy individuals - The HUNT study.J Mol Cell Cardiol2016;97:162-8

[180] Kukreja RC,Salloum FN.MicroRNAs: new players in cardiac injury and protection.Mol Pharmacol2011;80:558-64 PMCID:PMC3187527

[181] Aonuma T,Kawaguchi S.Cardiomyocyte microRNA-150 confers cardiac protection and directly represses proapoptotic small proline-rich protein 1A.JCI Insight2021;6:e150405 PMCID:PMC8492334

[182] Liu B,Lan M,Liu J.MicroRNA-21 mediates the protective effects of salidroside against hypoxia/reoxygenation-induced myocardial oxidative stress and inflammatory response.Exp Ther Med2020;19:1655-64 PMCID:PMC7027140

[183] Yin C,Kukreja RC.Endogenous microRNAs induced by heat-shock reduce myocardial infarction following ischemia-reperfusion in mice.FEBS Lett2008;582:4137-42 PMCID:PMC3031789

[184] Gao S,Dai L.miR-126 regulates angiogenesis in myocardial ischemia by targeting HIF-1α.Exp Cell Res2021;409:112925

[185] Li N,Tang Q.miR-133: A Suppressor of Cardiac Remodeling?.Front Pharmacol2018;9:903 PMCID:PMC6107689

[186] Niccoli T.Ageing as a risk factor for disease.Curr Biol2012;22:R741-52

[187] Crimmins EM.Lifespan and healthspan: past, present, and promise.Gerontologist2015;55:901-11 PMCID:PMC4861644

[188] Yoshida Y,Daimon M.Alteration of cardiac performance and serum B-type natriuretic peptide level in healthy aging.J Am Coll Cardiol2019;74:1789-800

[189] Schafer MJ,Kumar A.The senescence-associated secretome as an indicator of age and medical risk.JCI Insight2020;5:133668 PMCID:PMC7406245

[190] Madonna R.Cellular aging and rejuvenation in ischemic heart disease: a translation from basic science to clinical therapy.J Cardiovasc Aging2022;2:12

[191] Dipchand AI.Current state of pediatric cardiac transplantation.Ann Cardiothorac Surg2018;7:31-55 PMCID:PMC5827130

[192] Almond CSD,Piercey GE.Waiting list mortality among children listed for heart transplantation in the United States.Circulation2009;119:717-27 PMCID:PMC4278666

[193] Lipshultz SE,Asante-Korang A.Cardiomyopathy in children: classification and diagnosis: a scientific statement from the American heart association.Circulation2019;140:e9-68

[194] Broch K,Andreassen AK,Aakhus S.Contemporary outcome in patients with idiopathic dilated cardiomyopathy.Am J Cardiol2015;116:952-9

[195] Garcia AM,Nakano SJ.Heart failure in single right ventricle congenital heart disease: physiological and molecular considerations.Am J Physiol Heart Circ Physiol2020;318:H947-65 PMCID:PMC7191494