| High plasma level of oxidatively modified low density lipoprotein (ox-LDL) is a major risk factor for atherosclerosis. Of multiple receptors for ox-LDL on vessel wall components, lectin-like ox-LDL receptor-1 (LOX-1) plays a central role in atherosclerosis and associated complications. In these studies, we examined several aspects of LOX-1 biology.; In the first study, the role of LOX-1 in ox-LDL-induced apoptosis was studied in human coronary artery endothelial cells (HCAECs). We observed that ox-LDL induced apoptosis in HCAECs by activating caspase-9 and caspase-3. Ox-LDL induced a release of activators of caspase-9, including cytochrome C and Smac. Ox-LDL decreased the expression of anti-apoptotic proteins Bcl-2 and c-IAP-1, which are involved in the release of cytochrome C and Smac, and activation of caspase-9. More importantly, we identified that these pro-apoptotic effects of ox-LDL were mediated via LOX-1.; In the second study, the role of LOX-1 in hyperlipidemia-induced atherosclerosis was studied in apolipoprotein E (Apo-E) deficient mice. Administration of either rosuvastatin, a HMG CoA reductase inhibitor, or candesartan, an angiotensin II (Ang II) type 1 receptor blocker, attenuated p38 MAPK activation and LOX-1 expression, and reduced atherosclerosis. Importantly, concurrent therapy with both agents completely inhibited p38 MAPK activation and LOX-1 expression, and totally blocked atherosclerosis.; In the last study, we analyzed the promoter of human LOX-1 gene in HCAECs. We observed that the nucleotide sequence between nt -35 and +36 was required for LOX-1 basal promoter activity. More importantly, we found that the nucleotide sequence between nt -1599 and -1494 was required for LOX-1 promoter activation in response to ox-LDL. Transcription factor Oct-1 binding site was localized in this region and may play a key role in ox-LDL-induced LOX-1 promoter activation. In contrast, we found that the nucleotide sequence between nt -2247 and -2131 was required for LOX-1 promoter activation in response to Ang II. Transcription factor NF-kappaB binding site was localized in this region and may play a key role in Ang II-induced LOX-1 promoter activation.; These studies suggest a central role of LOX-1 in atherogenesis. Understanding the mechanisms for LOX-1 gene expression may provide novel therapeutic strategies against atherosclerosis and associated diseases. |
