Elastogenesis in human arterial disease: a role for macrophages in disordered elastin synthesis.
OBJECTIVE
Elastin, an extracellular matrix protein, constitutes about 30% of the dry weight of the arteries. Elastolysis induced by inflammatory processes is active in chronic arterial diseases. However, elastogenesis in arterial diseases has received little attention. In this work we hypothesized that disordered elastogenesis is active in matrix remodeling in atheroma and abdominal aortic aneurysm (AAA).


RESULTS
Human AAA and atheroma have 4- to 6-fold more tropoelastin protein than nondiseased arteries. The smooth muscle cell-containing media and fibrous cap of atherosclerotic arteries contain ordered mature elastin, whereas macrophage (MPhi)-rich regions often have disorganized elastic fibers. Surprisingly, in addition to smooth muscle cells, MPhis in diseased arteries also produce the elastin precursor tropoelastin, as shown by double immunostaining, in situ hybridization, and reverse transcription-polymerase chain reaction for tropoelastin mRNA. Cultured monocyte-derived MPhis can express the elastin gene. AAA have 9-fold but atheroma only 1.6-fold lower levels of desmosine, a marker for mature cross-linked elastin, than normal arteries.


CONCLUSIONS
This study demonstrates ongoing but often ineffective elastogenesis in arterial disease and establishes human macrophages as a novel source for this important matrix protein. These results have considerable import for understanding mechanisms of extracellular matrix remodeling in arterial diseases.
Krettek
Alexandra
A
Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Eugene Braunwald Research Center 307, Boston, Mass 02115, USA.
Sukhova
Galina K
GK
Libby
Peter
P
D001011:Aorta / Q000737:chemistry / Q000166:cytology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured / Q000378:metabolism; D003895:Desmosine / Q000032:analysis; D004549:Elastin / Q000096:biosynthesis*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008264:Macrophages / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014333:Tropoelastin / Q000235:genetics
D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D014333:Tropoelastin; D003895:Desmosine; D004549:Elastin