title: Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis.
abstract: OBJECTIVE
  The factors mediating the paracrine effects of perivascular adipose tissue (PVAT) in atherosclerosis are largely unknown. The adipokine leptin has been implicated in the increased cardiovascular risk in obesity and may locally promote neointima formation independently of circulating leptin levels. In patients with established coronary artery disease, we examined the expression of leptin as well as of its possible inducers in 'cardiac' PVAT surrounding the aortic root and coronary arteries (C-PVAT), and compared it to the PVAT surrounding the internal mammary artery (IMA-PVAT), a vessel resistant to atherosclerosis.
  
  
  RESULTS
  Tissue specimens collected from male patients undergoing coronary artery bypass surgery were processed for real-time PCR, ELISA, in situ hybridization, and immunohistochemistry analysis. Leptin protein expression was elevated in C-PVAT compared to IMA-PVAT, independent of serum leptin levels. Compared to IMA-PVAT, C-PVAT exhibited more pronounced angiogenesis and inflammation, as indicated by significantly higher numbers of PECAM1-positive vessels and CD68-positive macrophages, and was characterized by a greater extent of fibrosis and hypoxia. Increased expression of hypoxia-inducible factor-1α and Fos-like antigen (FOSL)2, factors known to enhance leptin gene transcription, was observed in C-PVAT. As a proof of concept, exposure of human adipocytes to chemical hypoxia resulted in significantly increased FOSL2 and leptin mRNA levels.
  
  
  CONCLUSIONS
  A higher degree of local tissue hypoxia and up-regulation of leptin expression in the perivascular adipose tissue, along with increased vascularization, inflammation, and fibrosis, may contribute to the increased atherosclerotic plaque burden in the coronary arteries compared to the IMA.
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.|Center for Cardiology, Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Drosos
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Chalikias
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Pavlaki
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kareli
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Grigorios
authors.initials: G
authors.lastname: Epitropou
authors.affiliation: Department of Cardiovascular Surgery, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Bougioukas
authors.affiliation: Department of Cardiovascular Surgery, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mikroulis
authors.affiliation: Department of Cardiovascular Surgery, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Fotios
authors.initials: F
authors.lastname: Konstantinou
authors.affiliation: Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.affiliation: Laboratory of Molecular Haematology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Ritis
authors.affiliation: Center for Cardiology, Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tziakas
authors.affiliation: Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.|Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Stavros
authors.initials: S
authors.lastname: Konstantinides
authors.affiliation: Center for Cardiology, Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. katrin.schaefer@unimedizin-mainz.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D042501:Angiogenic Proteins / Q000032:analysis; D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008323:Mammary Arteries / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D019899:Paracrine Communication; D058226:Plaque, Atherosclerotic; D011446:Prospective Studies; D015854:Up-Regulation
chemical_list: D042501:Angiogenic Proteins; D015415:Biomarkers; D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D020738:Leptin
keywords: Coronary artery disease; FOSL2; Leptin; Obesity; Perivascular adipose tissue