Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions

PLoS One. 2013 Dec 13;8(12):e82243. doi: 10.1371/journal.pone.0082243. eCollection 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / pathology
  • Carrier Proteins / blood*
  • Carrier Proteins / genetics
  • Demography
  • Elastic Tissue / metabolism
  • Extracellular Matrix Proteins / blood*
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glycoproteins / blood*
  • Glycoproteins / genetics
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Myocardial Infarction / blood
  • Myocardial Infarction / genetics
  • Myocardial Infarction / pathology
  • Organ Specificity* / genetics
  • Osteopontin / blood
  • Osteoprotegerin / blood
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Statistics, Nonparametric


  • Carrier Proteins
  • Extracellular Matrix Proteins
  • Glycoproteins
  • MFAP4 protein, human
  • Osteoprotegerin
  • RNA, Messenger
  • Osteopontin

Grant support

The project was supported by the Danish Strategic Research Council, Centre of COPD research (www.cekol.dk) and the Carlsberg Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.