Expression of heregulin in human coronary atherosclerotic lesions.
BACKGROUND
Endothelial cells, monocytes/macrophages, and vascular smooth muscle cells contribute to the establishment and progression of atherosclerotic lesions by expressing growth and inflammatory factors. The aim of the present study was to determine whether heregulin (HRG) is associated with human coronary artery disease.


METHODS
Twenty-six fresh human coronary artery segments were collected at autopsy. Expression of cysteine-rich 61 (CYR61) and VEGF in response to HRG was studied in the human endothelial cell line EA.hy926, and expression of CYR61 and HRG was evaluated in activated macrophages isolated from peripheral blood of healthy donors.


RESULTS
We found that HRG was overexpressed at the protein and mRNA level in all lesions analyzed and gradually increased as the stages of the lesions progressed. Expression of HRG was observed in the intima primarily in macrophages. The same specimens were analyzed for the expression of CYR61, an angiogenetic factor regulated by HRG in breast cancer epithelial cells. CYR61 was expressed in both normal and atheromatic specimens, but its expression was significantly enhanced in macrophages of the intima. Activation of primary human macrophages results in increased expression of both HRG and CYR61. In addition, studies in endothelial cells where no endogenous HRG is present showed that HRG induces expression of CYR61 and secretion of VEGF.


CONCLUSIONS
HRG may, therefore, play an important role in the development of coronary artery disease and the expansion of the atherosclerotic plaque and may locally regulate the expression of the angiogenetic factor CYR61.
Panutsopulos
Dimitrios
D
Laboratory of Virology, Medical School, University of Crete, Heraklion, Greece.
Arvanitis
Dimitrios L
DL
Tsatsanis
Christos
C
Papalambros
Efstathios
E
Sigala
Fragiska
F
Spandidos
Demetrios A
DA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D055515:Cysteine-Rich Protein 61; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A