Ahmed Waleed, Orasanu Gabriela, Nehra Vedika, Asatryan Liana, Rader Daniel J, Ziouzenkova Ouliana, Plutzky Jorge
Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Circ Res. 2006 Mar 3;98(4):490-8. doi: 10.1161/01.RES.0000205846.46812.be. Epub 2006 Jan 26.
Although high-density lipoprotein (HDL) is known to inhibit endothelial adhesion molecule expression, the mechanism for this anti-inflammatory effect remains obscure. Surprisingly, we observed that HDL no longer decreased adhesion of U937 monocytoid cells to tumor necrosis factor (TNF)alpha-stimulated human endothelial cells (EC) in the presence of the general lipase inhibitor tetrahydrolipstatin. In considering endothelial mechanisms responsible for this effect, we found that endothelial lipase (EL) overexpression in both EC and non-EL-expressing NIH/3T3 mouse embryonic fibroblasts cells significantly decreased TNFalpha-induced VCAM1 expression and promoter activity in a manner dependent on HDL concentration and intact EL activity. Given recent evidence for lipolytic activation of peroxisome proliferator-activated receptors (PPARs)-nuclear receptors implicated in metabolism, atherosclerosis, and inflammation-we hypothesized HDL hydrolysis by EL is an endogenous endothelial mechanism for PPAR activation. In both EL-transfected NIH cells and bovine EC, HDL significantly increased PPAR ligand binding domain activation in the order PPAR-alpha> >-gamma>-delta. Moreover, HDL stimulation induced expression of the canonical PPARalpha-target gene acyl-CoA-oxidase (ACO) in a PPARalpha-dependent manner in ECs. Conditioned media from EL-adenovirus transfected cells but not control media exposed to HDL also activated PPARalpha. PPARalpha activation by EL was most potent with HDL as a substrate, with lesser effects on LDL and VLDL. Finally, HDL inhibited leukocyte adhesion to TNFalpha-stimulated ECs isolated from wild-type but not PPARalpha-deficient mice. This data establishes HDL hydrolysis by EL as a novel, distinct natural pathway for PPARalpha activation and identifies a potential mechanism for HDL-mediated repression of VCAM1 expression, with significant implications for both EL and PPARs in inflammation and vascular biology.
尽管已知高密度脂蛋白（HDL）可抑制内皮黏附分子的表达，但其抗炎作用的机制仍不清楚。令人惊讶的是，我们观察到在存在通用脂肪酶抑制剂四氢脂抑素的情况下，HDL不再降低U937单核细胞样细胞与肿瘤坏死因子（TNF）α刺激的人内皮细胞（EC）的黏附。在考虑负责这种作用的内皮机制时，我们发现内皮脂肪酶（EL）在EC和不表达EL的NIH/3T3小鼠胚胎成纤维细胞中的过表达，以依赖HDL浓度和完整EL活性的方式显著降低了TNFα诱导的VCAM1表达和启动子活性。鉴于最近有证据表明过氧化物酶体增殖物激活受体（PPARs）（参与代谢、动脉粥样硬化和炎症的核受体）的脂解激活，我们推测EL对HDL的水解是PPAR激活的一种内源性内皮机制。在EL转染的NIH细胞和牛EC中，HDL以PPAR-α>>-γ>-δ的顺序显著增加PPAR配体结合域的激活。此外，HDL刺激以PPARα依赖的方式在EC中诱导典型的PPARα靶基因酰基辅酶A氧化酶（ACO）的表达。来自EL腺病毒转染细胞的条件培养基，但不是暴露于HDL的对照培养基，也激活了PPARα。以HDL作为底物时，EL对PPARα的激活最为有效，对LDL和VLDL的影响较小。最后，HDL抑制白细胞与从野生型而非PPARα缺陷小鼠分离的TNFα刺激的EC的黏附。这些数据确立了EL对HDL的水解是PPARα激活的一种新的、独特的天然途径，并确定了HDL介导的VCAM1表达抑制的潜在机制，这对EL和PPARs在炎症和血管生物学中的作用具有重要意义。
