Decreased Expression of Insulin-like Growth Factor-1 and Apoptosis of Vascular Smooth Muscle Cells in Human Atherosclerotic Plaque

Abstract

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.