Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque.
Insulin-like growth factor-1 (IGF-1) plays an important role in migration, cell cycle progression and survival of vascular smooth muscle cells (VSMC). We investigated the specific localization of IGF-1 and its receptor (IGF-1R) and their association with apoptosis and the expression of apoptosis-related proteins in early and advanced atherosclerotic lesions. Human atherosclerotic plaques (n=23) from patients undergoing aortic, carotid or femoral arterial surgery were studied. Immunohistochemistry and in situ hybridization revealed significantly higher expression of IGF-1 and IGF-1R in the media than in the intima of early atherosclerotic lesions (P<0.01). Medial VSMC positive for BAX, a proapoptotic protein of the B-cell CLL/lymphoma 2 (BCL2) family, showed colocalization of IGF-1. Apoptosis, as detected by DNA in situ terminal deoxynucleotidyl transferase end labeling (TUNEL), was not present in these early lesions. In advanced atherosclerotic plaques, the expression of IGF-1 and IGF-1R was significantly lower in the intimal regions with macrophage infiltration than in those without macrophage infiltration or than in the media (P<0.01). Furthermore, IGF-1 and IGF-1R immunoreactivity was markedly lower in intimal TUNEL-positive VSMC compared with intimal BAX-positive and medial VSMC (P<0.01). We conclude that IGF-1 and IGF-1R expression are reduced in the deep intima of early atherosclerotic lesions and in areas of advanced plaques with macrophage infiltration. Since IGF-1 is a potent survival factor for VSMC, poor expression of IGF-1 and IGF-1R in intimal regions with macrophage infiltration would likely contribute to triggering VSMC apoptosis potentially leading to plaque weakening, plaque rupture and acute coronary events.
Okura
Y
Y
Division of Cardiology, University Hospital of Geneva, Geneva, Switzerland.
Brink
M
M
Zahid
A A
AA
Anwar
A
A
Delafontaine
P
P
D000368:Aged; D017209:Apoptosis; D001161:Arteriosclerosis / Q000473:pathology*; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1