Palfi Anita, Toth Ambrus, Hanto Katalin, Deres Peter, Szabados Eszter, Szereday Zoltan, Kulcsar Gyozo, Kalai Tamas, Hideg Kalman, Gallyas Ferenc, Sumegi Balazs, Toth Kalman, Halmosi Robert
First Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, 13 Ifjusag str., H-7624 Pecs, Hungary.
J Mol Cell Cardiol. 2006 Jul;41(1):149-59. doi: 10.1016/j.yjmcc.2006.03.427. Epub 2006 May 23.
The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.
通过Akt或蛋白激酶C（PKC）磷酸化抑制糖原合酶激酶-3β（GSK-3β），或激活丝裂原活化蛋白激酶（MAPK）级联反应，在心肌梗死后的左心室重塑中可能起关键作用。我们之前的数据表明，聚（ADP-核糖）聚合酶（PARP）抑制可调节MAPK和磷脂酰肌醇-3-激酶/Akt信号通路，这增加了PARP抑制剂可能对心脏肥厚信号反应产生有利影响的可能性。在异丙肾上腺素诱导的心肌梗死所致慢性心力衰竭大鼠模型中，对一种新型PARP抑制剂（L-2286）进行了测试。随后，评估了心脏肥厚和间质胶原沉积情况；此外，监测了线粒体酶活性以及GSK-3β、Akt、PKC和MAPK级联反应的磷酸化状态。PARP抑制剂（L-2286）治疗显著减轻了梗死后心力衰竭的进展，减轻了心脏肥厚和间质纤维化，并维持了呼吸复合体的完整性。更重要的是，L-2286抑制了与肥厚相关的泛PKC、PKCα/βII、PKCδ和PKCε磷酸化增加，而这些磷酸化增加可能是导致抗肥厚性GSK-3β激活的原因。这项研究首次证明，在慢性心力衰竭大鼠模型中，PARP抑制可有益地调节PKC/GSK-3β细胞内信号通路，从而确定了一个治疗心力衰竭的新药物靶点。
