Calabresi Laura, Rossoni Giuseppe, Gomaraschi Monica, Sisto Francesca, Berti Ferruccio, Franceschini Guido
Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano, Italy.
Circ Res. 2003 Feb 21;92(3):330-7. doi: 10.1161/01.res.0000054201.60308.1a.
The incidence and severity of primary cardiac events are inversely related to the plasma concentration of high-density lipoproteins (HDLs). We investigated whether HDLs may exert a direct cardioprotection in buffer-perfused isolated rat hearts, which underwent a 20-minute low-flow ischemia followed by a 30-minute reperfusion. The administration of HDLs at physiological concentrations (0.5 and 1.0 mg/mL) during the 10 minutes immediately before ischemia rapidly and remarkably improved postischemic functional recovery and decreased creatine kinase release in the coronary effluent. Reconstituted HDLs containing apolipoprotein A-I (apoA-I) and phosphatidylcholine, but not lipid-free apoA-I or phosphatidylcholine liposomes, were also effective in protecting the heart from ischemia-reperfusion injury. HDLs at reperfusion were less effective than when given before ischemia. HDLs caused a dose-dependent reduction of ischemia-induced cardiac tumor necrosis factor-alpha (TNF-alpha) expression and content, which correlated with the improved functional recovery. A parallel increase of TNF-alpha release in the coronary effluent was observed, due to a direct binding of cardiac TNF-alpha to HDLs. Taken together, these findings argue for a cause-effect relationship between the HDL-mediated removal of TNF-alpha from the ischemic myocardium and the HDL-induced cardioprotection. Indeed, etanercept, a recombinant TNF-alpha-blocking protein, caused a dose-dependent improvement of postischemic functional recovery. HDLs also enhanced ischemia-induced prostaglandin release, which may contribute to the cardioprotective effect. A low plasma HDL level may expose the heart to excessive ischemia-reperfusion damage, and HDL-targeted therapies may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.
原发性心脏事件的发生率和严重程度与高密度脂蛋白（HDL）的血浆浓度呈负相关。我们研究了HDL是否能在缓冲灌注的离体大鼠心脏中发挥直接的心脏保护作用，这些心脏经历了20分钟的低流量缺血，随后是30分钟的再灌注。在缺血前10分钟内给予生理浓度（0.5和1.0mg/mL）的HDL，能迅速且显著地改善缺血后功能恢复，并减少冠状动脉流出液中肌酸激酶的释放。含有载脂蛋白A-I（apoA-I）和磷脂酰胆碱的重组HDL，但无脂质的apoA-I或磷脂酰胆碱脂质体，在保护心脏免受缺血-再灌注损伤方面也有效。再灌注时给予HDL的效果不如缺血前给予时。HDL导致缺血诱导的心脏肿瘤坏死因子-α（TNF-α）表达和含量呈剂量依赖性降低，这与功能恢复的改善相关。由于心脏TNF-α与HDL的直接结合，观察到冠状动脉流出液中TNF-α释放平行增加。综上所述，这些发现支持HDL介导的从缺血心肌中清除TNF-α与HDL诱导的心脏保护之间存在因果关系。事实上，重组TNF-α阻断蛋白依那西普导致缺血后功能恢复呈剂量依赖性改善。HDL还增强了缺血诱导的前列腺素释放，这可能有助于心脏保护作用。低血浆HDL水平可能使心脏易受过度的缺血-再灌注损伤，而针对HDL的治疗可能有助于诱导对缺血-再灌注损伤的即时或延迟心肌保护。
