Glucose-Oxidized Low-Density Lipoproteins Enhance Insulin-Like Growth Factor I-Stimulated Smooth Muscle Cell Proliferation by Inhibiting Integrin-Associated Protein Cleavage

Abstract

Prior published reports have demonstrated that glucose-oxidized low-density lipoproteins (g-Ox-LDL) enhance the proliferative response of vascular smooth muscle cells (SMC) to IGF-I. Our previous studies have determined that the regulation of cleavage of integrin-associated protein (IAP) by matrix-metalloprotease-2 (MMP-2) in diabetic mice in response to hyperglycemia is a key regulator of the response of SMC to IGF-I. Because chronic hyperglycemia enhances glucose-induced LDL oxidation, these studies were conducted to determine whether g-OxLDL modulates the response of SMC to IGF-I by regulating MMP-2-mediated cleavage of IAP. We determined that exposure of SMC to g-OxLDL, but not native LDL, was sufficient to facilitate an increase in cell proliferation in response to IGF-I. Exposure to an anti-CD36 antibody, which has been shown to inhibit g-OxLDLmediated signaling, inhibited the effects of g-OxLDL on IGF-I-stimulated SMC proliferation. The effect of g-OxLDL could be attributed, in part, to an associated decrease in proteolytic cleavage of IAP leading to increase in the basal association between IAP and Src homology 2 domain-containing protein tyrosine phosphatase substrate-1, which is required for IGF-I-stimulated proliferation. The inhibitory effect of g-OxLDL on IAP cleavage appeared to be due to its ability to decrease the amount of activated MMP-2, the protease responsible for IAP cleavage. In conclusion, these data provide a molecular mechanism to explain previous studies that have reported an enhancing effect of g-OxLDL on IGF-I-stimulated SMC proliferation. (Endocrinology 150: 1321-1329, 2009)

Effect of trenbolone acetate plus estradiol on transcriptional regulation of metabolism pathways in bovine liver

“…IGF-1 and IGF-2 have been shown to stimulate the migration and proliferation of smooth muscle cells, whereas IGF-1 is more potent in the postnatal phase than IGF-2 in the prenatal phase (33,34). This response can be modulated by binding of IGF to IGFBP.…”

CD47: a new player in phagocytosis and xenograft rejection

“…Although the relationship between apoptosis and CD47 is incompletely defined, several studies suggest that the progression of apoptosis is linked to the reduction of cellular CD47 levels independent of the apoptotic stimulus 29 . Although the mechanism underlying the reduction of CD47 on the surface of apoptotic cells is unknown, it is believed that protease cleavage 30 could be a possibility; as a result, the apoptotic cells will no longer provide an inhibitory signal for phagocytosis via SIRPα which will facilitate their uptake by macrophages.…”

Decreased CD47 expression during spontaneous apoptosis targets neutrophils for phagocytosis by monocyte-derived macrophages

“…Allen et al . showed that matrix metalloprotease 2 (MMP-2) cleaved CD47 (24), and proteolysis removed the SIRPα binding site (25). Human PMN contain MMP-2 in their secondary granules (26); however, proteolysis of CD47 by neutrophil MMP-2 has not been reported.…”