Jia Guanghong, Cheng Gang, Soundararajan Krish, Agrawal Devendra K
Department of Biomedical Science, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1051-7. doi: 10.1152/ajpheart.00801.2006. Epub 2006 Oct 13.
The balance between apoptosis and survival of vascular smooth muscle cells (VSMCs) in the fibrous cap appears to best correlate with plaque instability or stability and is controlled by growth factors and cytokines. We recently reported the inhibition of insulin-like growth factor (IGF)-I-induced proliferation and increase in apoptosis of VSMCs by atheroma-associated cytokines. Here we assessed the expression of IGF-I receptor (IGF-IR) in atherosclerotic plaques and in plaque VSMCs of asymptomatic and symptomatic patients with carotid stenosis and examined the effect of IGF-I, IL-12, and IFN-gamma on the expression of IGF-IR and IGF-binding protein (IGFBP)-3 in plaque VSMCs. We observed significantly lower density of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic nuclei and increased positive immunoreactivity to IGF-IR and mRNA transcripts of endogenous IGF-I and IGF-IR in asymptomatic than in symptomatic plaque VSMCs. Positive correlation was found between apoptosis and IGF-IR expression in asymptomatic (r(2) = 0.942) and symptomatic (r(2) = 0.908) plaque VSMCs. The specific binding of (125)I-labeled IGF-I was 3.7-fold higher in plaque VSMCs of asymptomatic patients than in symptomatic patients. IGF-I increased both IGF-IR mRNA transcripts and expression of IGFBP-3 in VSMCs of asymptomatic plaques. IL-12 and IFN-gamma decreased IGF-IR mRNA transcripts and further increased the expression of IGFBP-3 in asymptomatic VSMCs but had no effect in symptomatic VSMCs. These data suggest that the decreased expression of IGF-IR mRNA and increased expression of IGFBP-3 in carotid plaques of symptomatic patients could be due to atheroma-associated cytokines and this could result in plaque instability.
纤维帽中血管平滑肌细胞（VSMC）的凋亡与存活之间的平衡似乎与斑块的不稳定性或稳定性最为相关，且受生长因子和细胞因子的控制。我们最近报道了动脉粥样硬化相关细胞因子对胰岛素样生长因子（IGF）-I诱导的VSMC增殖的抑制作用以及VSMC凋亡的增加。在此，我们评估了无症状和有症状颈动脉狭窄患者的动脉粥样硬化斑块及斑块VSMC中IGF-I受体（IGF-IR）的表达，并研究了IGF-I、白细胞介素（IL）-12和干扰素（IFN）-γ对斑块VSMC中IGF-IR和IGF结合蛋白（IGFBP）-3表达的影响。我们观察到，与有症状的斑块VSMC相比，无症状的斑块VSMC中，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性凋亡细胞核的密度显著降低，而对IGF-IR以及内源性IGF-I和IGF-IR的mRNA转录本的阳性免疫反应性增加。在无症状（r² = 0.942）和有症状（r² = 0.908）的斑块VSMC中，凋亡与IGF-IR表达之间存在正相关。无症状患者斑块VSMC中¹²⁵I标记的IGF-I的特异性结合比有症状患者高3.7倍。IGF-I增加了无症状斑块VSMC中IGF-IR mRNA转录本和IGFBP-3的表达。IL-12和IFN-γ降低了无症状VSMC中IGF-IR mRNA转录本，并进一步增加了IGFBP-3的表达，但对有症状的VSMC没有影响。这些数据表明，有症状患者颈动脉斑块中IGF-IR mRNA表达的降低和IGFBP-3表达的增加可能归因于动脉粥样硬化相关细胞因子，这可能导致斑块不稳定。
