Abdalla Said, Fu Xuebin, Elzahwy Sherif S, Klaetschke Kristin, Streichert Thomas, Quitterer Ursula
Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Switzerland.
Cardiovasc Hematol Agents Med Chem. 2011 Jul 1;9(3):190-206. doi: 10.2174/187152511797037583.
Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol-blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure.
慢性压力超负荷和动脉粥样硬化是导致心脏肥大和心力衰竭的主要病因。然而，从肥大向心力衰竭转变的潜在机制尚未完全明确。我们分析了主动脉缩窄诱导的慢性压力超负荷小鼠心力衰竭的发展情况，并将结果与患有晚期动脉粥样硬化的老年载脂蛋白E缺陷小鼠进行比较。我们通过超声心动图和有创血流动力学分析心脏功能，并结合全面的基因芯片基因表达研究（GSE25765 - 8）。基因芯片数据显示，压力超负荷或晚期动脉粥样硬化诱导的心力衰竭发作伴随着参与脂肪合成、储存和氧化的关键脂质代谢酶的强烈上调。心脏脂质过载可能通过增强心肌细胞死亡参与心力衰竭的进展。心脏脂质代谢的上调与衰竭心脏的氧和ATP消耗有关，因为雷诺嗪的抗缺血治疗可使心脏脂质代谢正常化并改善心脏功能。反之，用胱胺进行轻度硫醇阻断抑制细胞呼吸和ATP生成会触发心脏脂质代谢并导致心力衰竭迹象。心力衰竭患者的心脏组织标本也显示关键脂肪代谢酶的蛋白质水平较高以及脂质蓄积。综上所述，我们的数据强烈表明心脏脂质代谢上调和心肌脂质过载是心力衰竭发展的基础。
