title: Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions.
abstract: Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Wulf-Johansson
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Sofie
authors.initials: S
authors.lastname: Lock Johansson
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Schlosser
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Trommelholt Holm
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark ; Centre for Individualized Medicine in Arterial Diseases (CIMA), Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark ; Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark.
authors.forename: Lars Melholt
authors.initials: LM
authors.lastname: Rasmussen
authors.affiliation: Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark ; Department of Cardiology, Odense University Hospital, Odense, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Mickley
authors.affiliation: Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark ; Department of Cardiology, Odense University Hospital, Odense, Denmark.
authors.forename: Axel C P
authors.initials: AC
authors.lastname: Diederichsen
authors.affiliation: Department of Cardiology, Lillebælt Hospital Vejle, Vejle, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Munkholm
authors.affiliation: Department of Cardiology, Odense University Hospital, Odense, Denmark.
authors.forename: Tina Svenstrup
authors.initials: TS
authors.lastname: Poulsen
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Tornøe
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Vicki
authors.initials: V
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.affiliation: Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark ; Respiratory and Allergy Research Group, Manchester Academic Health Sciences Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark ; Department of Clinical Immunology, Næstved Hospital, Næstved, Denmark.
authors.forename: Susanne Gjørup
authors.initials: SG
authors.lastname: Sækmose
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Uffe
authors.initials: U
authors.lastname: Holmskov
authors.affiliation: Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Grith Lykke
authors.initials: GL
authors.lastname: Sorensen
mesh_terms: D000368:Aged; D000818:Animals; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000097:blood* / Q000235:genetics; D003710:Demography; D004547:Elastic Tissue / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000097:blood* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000097:blood* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D053495:Osteopontin / Q000097:blood; D053244:Osteoprotegerin / Q000097:blood; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C400752:MFAP4 protein, human; D053244:Osteoprotegerin; D012333:RNA, Messenger; D053495:Osteopontin