Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
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DOI：
10.1172/jci42946
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Landmesser, Ulf
中科院分区：
文献类型：
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作者：
Besler, Christian;Heinrich, Kathrin;Landmesser, Ulf
正在检查正在检查或预防冠状动脉疾病（CAD）的治疗或预防冠状动脉（CAD）的疗法，被认为会通过对内皮作用发挥动脉保护作用的疗法。但是，HDL的内皮作用是高度异质的，并且HDL的CAD患者对内皮eNOS激活和依赖eNOS依赖性途径的影响尚不清楚。在这里，我们证明，与健康受试者的HDL相反，来自稳定CAD或急性冠状动脉综合征（HDLCAD）患者的HDL没有内皮抗炎作用，并且没有刺激内皮修复，因为它无法诱导内皮无生产。从机械上讲，这是因为HDLCAD激活的内皮凝集素样氧化的LDL受体1（LOX-1），触发内皮PKC Beta II激活，这又抑制了ENOS激活途径和ENOS依赖性依赖性无产生。然后，我们确定了降低的HDL相关二氧酮酶1（PON1）的活性是一种分子机制，导致HDL产生具有内皮PKCβII激活特性，至少部分是由于HDL中马其多醛的形成增加。综上所述，我们的数据表明，在CAD患者中，HDL获得了内皮LOX-1-，从而由于HDL相关的PON1活性而引起的PKC Beta II激活特性，这会导致抑制ENOS激活和随后的损失损失HDL的内皮抗炎和内皮修复刺激作用的作用。
Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKC beta II activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKC beta II-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKC beta II-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.