Role of IGFBP1 in the senescence of vascular endothelial cells and severity of aging-related coronary atherosclerosis

The senescence of vascular endothelial cells (ECs) plays a critical role in aging-related cardiovascular diseases. We previously reported the causal relation of Jagged1 in ECs and the thickening of the arterial wall in aging mice. The aim of the present study was to further investigate the correlation between insulin-like growth factor-binding protein 1 (IGFBP1), one of the secretory proteins regulated by Jagged1, and the severity of coronary atherosclerosis and patient age, as well as its effect on EC senescence. First, microarray analysis was performed to screen the differentially expressed genes regulated by Jagged1 in human coronary arterial ECs (HCAECs). Inhibition of the Jagged1 expression using a small interfering RNA knockdown method in HCAECs led to the upregulation of 17 and the downregulation of 78 genes by >3-fold, and IGFBP1 was confirmed to be a secretory protein expressed by HCAECs and regulated by Jagged1. Subsequently, in 112 consecutively enrolled patients with acute chest pain who underwent coronary angiography, the circulating level of IGFBP1 was found to be positively correlated with age (r=0.512, P<0.001) and Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) score (r=0.409, P<0.001). Among age-comparable patients, the circulating IGFBP1 level was found to be increased in patients with higher SYNTAX scores. In cultured HCAECs, IGFBP1 was shown to protect ECs against passage- or H(2)O(2)-induced senescence, and these protective effects of IGFBP1 may be partially reversed by LY294002, a known Akt signaling inhibitor. Therefore, the results of the present study suggested that, as a downstream protein of Jagged1, IGFBP1 was correlated with the severity of coronary atherosclerosis in aging patients, and the increase of circulating IGFBP1 levels with aging may be an adaptive response to counter HCAEC senescence through Akt signaling.