Linz Wolfgang, Wohlfart Paulus, Baader Manuel, Breitschopf Kristin, Falk Eugen, Schäfer Hans-Ludwig, Gerl Martin, Kramer Werner, Rütten Hartmut
Therapeutic Department Cardiovascular Diseases, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
Acta Pharmacol Sin. 2009 Jul;30(7):935-46. doi: 10.1038/aps.2009.58. Epub 2009 Jun 8.
To investigate the efficacy of the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, AVE8134, in cellular and experimental models of cardiac dysfunction and heart failure.
In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI), AVE8134 was compared to the PPARgamma agonist rosiglitazone and in a second study to the ACE inhibitor ramipril. In DOCA-salt sensitive rats, efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated. Finally, AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a non-blood pressure lowering dose with survival as endpoint. In cellular models, we studied AVE8134 on hypertrophy in rat cardiomyocytes, nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells.
In post-MI rats, AVE8134 dose-dependently improved cardiac output, myocardial contractility and relaxation and reduced lung and left ventricular weight and fibrosis. In contrast, rosiglitazone exacerbated cardiac dysfunction. Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio. In DOCA rats, AVE8134 prevented development of high blood pressure, myocardial hypertrophy and cardiac fibrosis, and ameliorated endothelial dysfunction. Compound treatment increased cardiac protein expression and phosphorylation of eNOS. In old SHR, treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure. AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes. In HUVEC, Ser-1177-eNOS phosphorylation but not eNOS expression was increased. In monocytes, AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1, resulting in enhanced uptake of oxidized LDL.
The PPARalpha agonist AVE8134 prevents post-MI myocardial hypertrophy, fibrosis and cardiac dysfunction. AVE8134 has beneficial effects against hypertension-induced organ damages, resulting in decreased mortality. The compound exerts its protective properties by a direct effect on cardiomyocyte hypertrophy, but also indirectly via monocyte signaling and increased endothelial NO production.Acta Pharmacologica Sinica (2009) 30: 935-946; doi: 10.1038/aps.2009.58; published online 8 June 2009.
研究过氧化物酶体增殖物激活受体α（PPARα）激动剂AVE8134在心脏功能障碍和心力衰竭的细胞及实验模型中的疗效。
在左冠状动脉永久结扎的Sprague Dawley大鼠（心肌梗死后）中，将AVE8134与PPARγ激动剂罗格列酮进行比较，并在第二项研究中与ACE抑制剂雷米普利进行比较。在去氧皮质酮盐敏感大鼠中，研究AVE8134对心脏肥大和纤维化的疗效。最后，以非降压剂量将AVE8134给予老年自发性高血压大鼠（SHR），以生存作为终点指标。在细胞模型中，我们研究了AVE8134对大鼠心肌细胞肥大、人内皮细胞（HUVEC）中一氧化氮信号传导以及人单核细胞系MonoMac-6细胞中低密度脂蛋白摄取的影响。
在心肌梗死后大鼠中，AVE8134剂量依赖性地改善心输出量、心肌收缩性和舒张功能，并减轻肺和左心室重量以及纤维化。相比之下，罗格列酮加剧了心脏功能障碍。AVE8134治疗可降低血浆前脑钠肽和精氨酸水平，并增加血浆瓜氨酸水平和尿中氮氧化物/肌酐比值。在去氧皮质酮大鼠中，AVE8134可预防高血压、心肌肥大和心脏纤维化的发展，并改善内皮功能障碍。联合治疗可增加心脏蛋白表达和内皮型一氧化氮合酶（eNOS）的磷酸化。在老年SHR中，低剂量的AVE8134治疗可改善心脏和血管功能，并延长预期寿命而不降低血压。AVE8134可减轻去氧肾上腺素诱导的成年大鼠心肌细胞肥大。在HUVEC中，Ser-1177-eNOS磷酸化增加，但eNOS表达未增加。在单核细胞中，AVE8134增加CD36和巨噬细胞清道夫受体1的表达，导致氧化型低密度脂蛋白摄取增加。
PPARα激动剂AVE8134可预防心肌梗死后心肌肥大、纤维化和心脏功能障碍。AVE8134对高血压引起的器官损伤具有有益作用，可降低死亡率。该化合物通过对心肌细胞肥大的直接作用以及通过单核细胞信号传导和增加内皮一氧化氮生成的间接作用发挥其保护特性。《中国药理学报》（2009年）30卷：935 - 946页；doi: 10.1038/aps.2009.58；2009年6月8日在线发表。
