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Background-We have recently demonstrated a lectin-like receptor for oxidized (ox)-LDL (LOX-1) in human coronary artery endothelial cells (HCAECs). This receptor is upregulated by ox-LDL. The present study examined the significance of LOX-1 in monocyte adhesion to HCAECs and endothelial injury in response to ox-LDL. Methods and Results-HCAECs were incubated in the presence of antisense oligodeoxynucleotides to the 5Ј-coding sequence of the human LOX-1 gene (0.5 m/L). Basal LOX-1 mRNA and protein were suppressed by antisense LOX-1. Ox-LDL-mediated upregulation of LOX-1 was also suppressed by antisense LOX-1. Incubation of HCAECs with ox-LDL (40 g/mL) for 24 hours markedly increased monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression as well as monocyte adhesion to HCAECs (PϽ0.01). After 48 hours of preincubation of HCAECs with antisense LOX-1, ox-LDL-mediated upregulation of MCP-1 and monocyte adhesion to HCAECs both were suppressed (PϽ0.01), whereas sense LOX-1 had no effect. Whereas antisense or sense LOX-1 alone (both 0.5 nmol/L) did not injure the cells, antisense LOX-1, but not sense LOX-1, reduced ox-LDL-mediated HCAEC injury, determined as LDH release (PϽ0.01). Activation of mitogen-activated protein kinase (MAPK) may play a critical role in signal transduction in ox-LDL-mediated alteration in MCP-1 expression, since antisense LOX-1, but not the sense LOX-1, completely inhibited the ox-LDL-induced MAPK activation. Conclusions-These observations with the first use of a specific antisense to human LOX-1 mRNA suggest that LOX-1 is a key factor in ox-LDL-mediated monocyte adhesion to HCAECs.

Green innovation is an important approach for achieving sustainable development. Most research on determinants of corporate green innovation has focused on either external or internal drivers. Combining institutional theory and resource-based view, the scientific value of this study lies in simultaneously exploring the influence of external legitimacy pressure and internal corporate profitability, and their interaction on green innovation. Samples of the top 100 listed companies in China, from 2008 to 2012, were used and the results demonstrated that legitimacypressure from stakeholders has a significantly positive influence on both corporate green product innovation and process innovation. The results also revealed that corporate profitability positively affects green product innovation, while there was found to be no significant influence on green process innovation. Moreover, corporate profitability positively moderates the relationship between legitimacy pressure and green product innovation. The results show that not only the single factor of external legitimacy pressure and internal profitability, but also their interaction, affects corporate green innovation practices. This offers an integrating perspective on how corporations can be more innovative in sustainability.

Abstract-A specific lectinlike endothelial receptor for oxidized low density lipoprotein (LOX-1), distinct from the scavenger receptor in monocytes/macrophages, has been identified and cloned. In this study, we examined the regulation of LOX-1 by oxidized low density lipoprotein (ox-LDL) and determined the role of LOX-1 in ox-LDL-induced apoptosis of cultured human coronary artery endothelial cells (HCAECs). Incubation of HCAECs with ox-LDL (40 g/mL), but not native LDL, for 24 hours markedly increased LOX-1 expression (mRNA and protein). After 48 hours of preincubation of HCAECs with a specific antisense to LOX-1 mRNA (antisense LOX-1), ox-LDL-mediated upregulation of LOX-1 was suppressed (PϽ0.01). In contrast, treatment of HCAECs with sense LOX-1 had no effect. Recent studies show that cytokine tumor necrosis factor (TNF)-␣ 4 and fluid shear stress 5 markedly upregulate LOX-1 gene expression in endothelial cells. Another study 6 has shown that LOX-1 expression is dramatically increased in hypertensive rats. A more recent study from our laboratory 7 has demonstrated that angiotensin II upregulates LOX-1 expression as well as the uptake of ox-LDL in human coronary artery endothelial cells (HCAECs).It is widely appreciated that LDL, especially its oxidatively modified form (ox-LDL), is a critical factor in atherogenesis.Endothelial dysfunction elicited by ox-LDL has been identified in the course of atherogenesis and its complications. 8 LDL is oxidized in vascular endothelial cells to a highly injurious product that results in characteristic cell dysfunction in large arteries and resistant vessels. Endothelial dysfunction (ie, loss of vasodilation, vasoconstriction, thrombosis, and inflammation) occurs before and throughout the development of atherosclerosis and particularly during plaque rupture. Ox-LDL appears to induce this cellular dysfunction in a timeand concentration-dependent manner. 9 Recent studies show that apoptosis, which is a common accompaniment of atherosclerosis, is induced by ox-LDL in cultured vascular smooth muscle cells, 10 monocytes/macrophages, 11 and human endothelial cells. 12 The mechanisms of ox-LDL-mediated apoptosis, particularly in endothelial cells, and of its relation with LOX-1 have not been defined.Nuclear factor (NF)-B, a transcription factor, regulates the transcription of a variety of cellular genes, including injury response and growth control. 13 Activation of NF-B is

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Abstract-Oxidized low-density lipoprotein (ox-LDL) induces apoptosis in endothelial cells. However, steps leading to ox-LDL-induced apoptosis remain unclear. We examined the role of ox-LDL and its newly described receptor LOX-1 in the expression of intracellular pro-and antiapoptotic proteins and caspase pathways in human coronary artery endothelial cells (HCAECs). Cells were cultured and treated with different concentrations (10 to 80 g/mL) of ox-LDL for different times (2 to 24 hours). Ox-LDL induced apoptosis in HCAECs in a concentration-and time-dependent manner. Ox-LDL also activated caspase-9 and caspase-3, but not caspase-8. After ox-LDL treatment, there was a significant release of activators of caspase-9, including cytochrome c and Smac from mitochondria to cytoplasmic compartment, and their release was not affected by treatment of cells with inhibitors of either caspase-8 or caspase-9. Ox-LDL also decreased expression of antiapoptotic proteins Bcl-2 and c-IAP (inhibitory apoptotic protein)-1, which are involved in the release of cytochrome c and Smac and activation of caspase-9, in a concentration-and time-dependent manner. On the other hand, ox-LDL did not change the expression of Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein (FLIP) and proapoptotic protein Fas, which are required for the activation of caspase-8. Further, ox-LDL did not cause the truncation of Bid, which implies the activation of caspase-8. In other experiments, pretreatment of HCAECs with the caspase-9 inhibitor z-LEHD-fmk, but not the caspase-8 inhibitor z-IETD-fmk, blocked ox-LDL-induced activation of caspase-3 and apoptosis. As expected, pretreatment with the caspase-3 inhibitor DEVD-CHO inhibited ox-LDL-induced activation of caspase-3 and resultant apoptosis. The proapoptotic effects of ox-LDL were mediated by its receptor LOX-1, because pretreatment of HCAECs with antisense-LOX-1, but not sense-LOX-1, blocked these effects of ox-LDL. These findings suggest that ox-LDL through its receptor LOX-1 decreases the expression of antiapoptotic proteins Bcl-2 and c-IAP-1. This is followed by activation of apoptotic signaling pathway, involving release of cytochrome c and Smac and activation of caspase-9 and then caspase-3. (Circ Res. 2004;94:370-376.)